I And I Exam 1

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Antiseptic

Back 1

Any chemical agent usually applied to living tissues that prevents the growth of microorganisms on living tissue

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Disinfectant

Back 2

A chemical agent capable of killing pathogenic microorganisms on inanimate material

Front 3

Asepsis

Back 3

The prevention of contact with pathogens

Front 4

Bactericidal

Back 4

Killing of bacteria

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Bacteriostatic

Back 5

Stopping the growth of bacteria

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Cross-Infection

Back 6

The transmission of pathogenic or potentially pathogenic microorganisms from one patient to another

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Sanitizers

Back 7

Agents used for the Removal of microflora and debris

Front 8

Sepsis

Back 8

The presence of pathogenic or potentially pathogenic microorganisms in blood or other tissues

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Sterilization

Back 9

Complete destruction of all life

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Factors Affecting Microbial Death

Back 10

1). Nature of the organism-spore formers. The most resistance form of life is Mycobacterium tuberculosis. 2). Concentration of agent 3). Temperature 4). Effect of organic matter and pH 5). Concentrations of cells 6). Time

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Sterilization Methods

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1). Autoclaving (121 degrees celsius, 15PSI (2atm), 15 min): Denaturation 2). Dry heat (160 degrees celcius for 2 hr or 171 degrees celcius for 1 hr): Oxidation 3). Radiation: DNA inactivation, peroxide formation a). UV light 2). Ionizing Radiation (x-rays and gamma rays) c). Deinococus radiodurans is the industry index

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Sterilizatoin Methods Cont'd

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4). Filtration: 0.22micrometer or smaller porosity 5). Unsaturated chemical vapor (chemicalve): 132 degrees celcius, 20 min: Protein denaturation, alkylation. 6). Ethylene oxide (R.T-50 degrees celcius 3-24 hrs): Protein alkylation

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Ineffective Sterilization Methods

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1). Freeze-thaw 2). Drying (dessication) 3). Ultrasonic Oscillation (cold sterilization)

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Sterilization Quality Assurance

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1). Process indicators: a). Autoclave tape b). Temperature recorders 2). Biological Indicators a). Spore containing ampules b). Spore bacterial test strips c). Bacillus stearothermophilus is the industry index for heat killing (Use once a week and place inside a pack)

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Spore-Containing Vile

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Contains an outer vial, an inner vial with media, and a paper strip with pores.
Steps: 1). Autoclave 2). Break inner vial 3). Incubate at 55-60 degrees celcius for 2 days.

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Microbe(Bacterial)---Route of Transmission--Estimated Surface Survival

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1). Myobacterium tuberculosis--Saliva, sputum--Months 2). Staphylococcus aureus--Saliva, exudates, skin--Days

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Microbe (Viral)--Route of Transmission--Estimated Surface Survival

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1). HSV--Saliva, secretions--Minutes 2). Influenza--Saliva, secretions--Hours 3). Hepatitis A--Blood, feces--Days 4). HIV--Blood, semen, secretions--Days 5). Hepatitis B--Blood Saliva--Months

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Disinfection Agents

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1). Halogens (iodophors, sodium hypochlorite (bleach)) 2). Glutaraldehyde (alkylate and denature proteins) 3). Surfactants (denature proteins, disrupt membranes) 4). Alcohols (denature proteins and disrupt membranes)

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Measurement of Disinfection

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Myobacterium tuberculosis--the industry index for chemical killing; It's standard levels of activity are High for Vegetative, Fungi, TB Bacillus, Viruses, and Spores; Medium for Vegetative, Fungi, TB Bacillus, and Viruses; and Low for Vegetative and Fungi

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Disinfection vs. Sterilization

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1). Critical--Instruments that will touch bone or penetrate tissue--forceps, scalpels, and scalers--sterilize 2). Semi-critical--instruments that will touch mucuous membranes--mirrors and amalgam condensers--sterilize or high level disinfect 3). Non-critical--instruments or surfaces that contact only intact skin--chairs and counter tops--disinfect

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Quality Insurance for Disinfection

Back 21

None

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Dentistry and Asepsis

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Anything that goes in the mouth should be disposable, disinfected, or sterilized after use
Universal barrier precautions should be used on a per patient basis: mask, gloves, eye protection
Hands should be washed well whenever gloves are changed.
If hands are not visibly soiled, can use alcohol-based sanitizers (60-95% alcohol).

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Hand Washing

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1). Hands are the most common mode of pathogen transmission 2). CDC estimates that each year nearly 2 million patients in the United States acquire infections in hospitals, and about 90,000 of these patients die as a result.

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STEAMplus

Back 24

Engineered to employ all 3 critical parameters of sterilization: Saturated Steam, Time, and Temperature.

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Hand Hygeine Definitions

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1). Handwashing--washing hands with plain soap and water 2). Antiseptic handwash--Washing hands with water and soap or other detergents containing an antiseptic agent 3). Alcohol-based handrub--Rubbing hands with an alcohol containing prep 4). Surgical antisepsis--handwashing with an antiseptic soap or an alchohol based handrub before operations by surgical personnel

The best is alcohol-based handrub

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Alcohol based Handrubs

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Benefits: 1). Rapid and effective antimicrobial action 2). Improved Skin Condition 30. More accessible than sinks
Limitations: 1) .Cannot be used if hands are visibily soiled 2). Store away from high temps or flames 3). Hand softeners and glove powders may build up 4). Stuides have shown that 62% ethanol is superior to 40% ethanol but discount brands may offer only 40 % ethanol and/or ma not display this level. It was actually found in one study that this level of ethanol actually increased microbial concentration.

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Asepsis and Dentistry Cont'd

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1). Foot control for instrumentation/equiptment where possible 2). Disposable plastic coverings on instrumentation/equiptment/handles 3). Disinfection agents should be properly labeled 4). Dental team should be vaccinated against Hep B virus

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Avg. Risk of Bloodborne Virus Transmission after Needlestick

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1). HBV---HBsAG+ and HBeAg+--22-31% clinical hepatitis; 37-62% serological evidence of HBV infection
2). HBV--HBsAg+ and HBeAg- -- 1-6% clinical hep; 23-37% serological evidene of HBV infection
3). HCV--1.8%
4). HIB--0.3%

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Concentration of HBV in Body Fluids

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1). High--blood, serum, and wound exudates 2). Moderate--Semen, vaginal fluid, saliva 3). Low--Urine, feces, sweat, tears, and breast milk

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Estimated Incidence of HBV Infections Among Health Care Professionals and General Population

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1). Has dropped significantly in the HCP from 1985 to 1999 2). Dropped a little in the general US Population

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Transmission of HBV from infected DHCP to Patients

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1). From 1970-1987 nine clusters of transmission were reported 2). 8 Dentists tested for HBeAg were positive 3). The one and only case of patient to patient transmission was in 2003

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Transmission of HIV from Dentist to Patient

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Has only happened once

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Asepsis at VCU

Back 33

Target 0--The school of dentsitry's school wide campaign to reduce occupational exposures to bloodborne pathogens.
Why?--From 7/1/08 through 4/20/09 there were 30 blood and body fluid exposures reported for the students, staff, residents and faculty. The most common were: needle stick (9), bur stick (7), instruement stick (4), scalpel/knife (4), and Matrix Band (3).

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Survival of HIV outside the body

Back 34

Scientists agree that HIV does not survive well outisde the body, making the possibility of environmental and transmission remote. However unnatural concentrations of HIV can be kept alive for days or even weeks under precisely controlled and limited laboratory conditions.
Results from lab studies should not be used to assess specific personal risk of infection because noone has been identified as infected with HIV due to contact with an environmental suface. Also HIV is unable to reproduce outside its living host.

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Bacterial Growth

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Growth--increase in size and numbers of bacterial cells (and therefore increase in bacterial mass);
Usually determined a). in liquid culture techniques to measure cell numbers (direct microscopic counts, viable cell counts Coulter counter) b). Cell Mass (turbidity, pellet weight, protein content).

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Types of Microbial Growth

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1). Bacteria--binary fission (identical offspring) 2). Yeast--budding 3). Protozoa--sexual and asexual reproduction

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4 Phase of Bacterial Growth

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1). Lag --adaptation to new medium
2). Log--balanced inc. in all cell constituents, with log increase in cell population---most important 3). Stationary--nutrient limitation, accumulation of toxi products, pH change, reduced oxygen tension 4). Death--time of onset and rateof cell killing differs for various bacteria

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Growth Rate (Bacterial Growth)

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The Growth Rate--or doubling time--is determined by the typ of organism, nature of the medium, and environmental factors;
1). The fastest maximal double times around 10 to 12 mins by Clostridium perfringens and various marine vibrios suchas Vibrio parahaemolyticus or V. vulnificus. Escherchia and Salmonella have max. doubling times of 20 to 30 mins.
2). Slowest generaton times of up to 24 hours for Mycobacterium tuberculosis.

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E. Coli Growth

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It has been calculated that if an organism such as E. coli were provided with all essential nutrients and optimum growth conditions for maximum rates of growth, the yield of the cells after 48hrs could outweigh the mass of the Earth

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Factors affecting Bacterial Growth

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1). Oxygen tension 2). pH 3). Temperature

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Oxygen Requirements

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1). Obligate Aerobes--need 20% oxygen to grow--respiratory metabolism
2). Obligate Anaerobes--only grown in reduced oxygen--respiratory and fermentative metabolism 3). Facultative Anaerobes--grow either situation 4). Nanaerobes--grow in low concentrations (6%).

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Oxygen Toxicity

Back 42

The aerobic lifestyle is the basis for oxygen toxicity;
Hydrogen peroxide reacts with O2- to form hydroxyl radical (OH) which is extremely reactive and can damage DNA, proteins, and membranes. ;
Enzymes are able to inactivate the toxic byproducts: 1). Catalase 2). Peroxidase 3). Superoxide dismutase

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Oxygen Toxicity Cont'd

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In general, 1). Aerobes possess all 3 enzymes 2). Aerotolerant organsisms lack catalase 3). Anaerobes often lack all 3

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Temperature Effect

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1). Most bacteria of medical importance are mesophiles (growth in 25-45 degrees celcius).
2). Other types are thermophiles (high) or psychrophiles (low)

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pH

Back 45

1). Most bacteria of medical importance grow best in a medium of pH 6.5 to 7.5
2). Neisseria, Bordetella, Pseudomonas and a few other pathogens grow within a narrow pH range
3). Streptococcus sp, and other lactic acid bacteria tolerate pH <4.5
4). Fungi grow well at pH 6.0-6.5

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Anabolism

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1). Biosynthesis 2). Energy is Used

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Catabolism

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1). Breakdown 2). ATP is generated 3). Generate energy and reducing power for synthesis of macromolecules essential for growth

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E. Coli Food Pyramid

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Almost 99% Sugar or protein or fats and the other 1% Inorganic Salts; It is very simple because it can make things for itself.

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Oxidation and Reduction

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1). Oxidation--Removal of electrons and hydrogens 2). Reduction--Addition of electrons and hydrogens; These are coupled reactions

Oxygen is usually a terminal electron acceptor

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NADH vs FADH

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1). NADH is converted into 3 ATP
2). FADH is converted into 2 ATP

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Phosphorylation

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1). Substrate Level--Glycolysis--results in the formation of ATP by direct transfer of phosphate
2). Oxidative Phosphorylation--Respiration (ETS)--metabolic pathway to produce ATP

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Respiration

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1). Aerobic: a). Oxygen is terminal electron acceptor b). requires ETS
2). Anaerobic--bacteria a). Other compound is terminal electron acceptor b). Requires ETS

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Fermentation

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Organic compound is the terminal electron acceptor

Front 54

Electron Acceptors Used in Respiration (Electon acceptor--reduced end product--name or process--organism)

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1). O2--H20--aerobic respiration--all aerobic bacteria, fungi, protozoa, and algea (Escherchia, Stretomyces)
2). NO3--NO2, NH3, or N2--anerobic respiration, denitrification--Enteric bacteria, Bacillus, Pseudomonas, and Paracoccus
3). SO4---S or H2S--Anaerobic respiration: sulfate reduction---Desulfovibrio and Desulfotomaculum 4). Fumarate--succinate--Anaerobic Respiration: Using an organic e acceptor--Escherichia, Porphyromonas, Bacteroides, Prevotella, Tanneralla
5). CO2--CH4--Anerobic Respiration: Methanogensis--All methanogens--Methanococcus

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Fermentation Cont'd

Back 55

1). Anaerobic Cells that cannot obtain energy via aerobic ETS (i.e. oxidative phosphorylation)
2). Rather than pyruvate eventually being metabolized via the TCA cycle, anaerobially grown cells reduce pyruvate to a large number of metabolic end products which turn out to be characteristic of specific bacterial species. Such anaerobic reactions use organic compounds as the ultimate electron acceptors instead of oxygen.
However, remember that anaerobic bacteria can grow through respiration.

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Anaerobic Fermentation

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1). Lacks a functional ETS (no oxidative phosphorylation).
2). Only uses step 1 (glycolysis)
3). 2 ATPs net (substrate level)
4). Uses 2 NADHs produced to reduce pyruvate to fermentation products
5). Most energy remains in fermentation products

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Variations to Metabolic Pathways

Back 57

1). Glycolysis (1 glucse> 2 pyruvates): a). Pentose Pathway (1 glucose >1 ribose-4-phosphate, NADPH) (hexose monophosphate shunt) (bacteria and eukaryotes). b). Entner-Doudoroff pathway (1 glucose > 1 pyruvate) (bacteria) c). heterofermentative pathways, such as phoshoketolase pathways (bacteria)
2). TCA cycle: a). Glyoxylate pathway (bacteria)

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Pentose Phosphate Pathway

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Glucose>>Glucose-6-Phosphate>>Ribulose-5-Phosphate>>Ribose-5-Phosphate

Front 59

Oxidative Pathways of glycolysis employed by various bacteria

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1). E. coli--Embeen-Meyerhof pathway; 2). Bacillus subtilis--Embden Meyerhof Pathway and Phosphoketolase Pathway.

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Kreb's Cycle

Back 60

1). Functions similarly in bacteria and eukaryotes however major difference may be found in bacteria----in obligate aerobes, L-malate may be oxidized directly by molecular oxygen via ETC. Also in some bateria some Krebs cycle intermediate reactions occur because a-ketoglutarate dehydrogenase is missing.

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Glyoxylate Cycle

Back 61

A modification of the Kreb's Cycle;
Acetyl Coenzyme A is generated directly from oxidation of fatty acids or other lipid compounds;
Occurs in some bacteria, used for metabolizing acetic acid or higher fatty acids;
Reaction products (malate and citrate) enter the TCA cycle.

Fatty Acids>>Acetyl-CoA>>Isocitrate>>Succinate>> Fumarate>>Gluconeogenesis

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ETS--Anaerobic Respiratoin

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1). Present in bacteria 2). reactions and steps similar to Aerobic Respiration (enzymes may differ) 3). Terminal Electron Acceptor--other than Oxygen 4). Less Efficient--usually 30-40ATP per glucose

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Prokaryotes vs. Eukaryotes

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Prokaryotes do not contain membrane bound organelles while Eukaryotes do.

Both contain ribosomes

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Cell Walls and Membranes of Prokaryotes and Eukaryotes

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1). Prokaryotes--cell wall made of peptidoglycan--protein-lipid bilayer without sterols
2). Eukaryotes--chitin cell walls (plant) and none for animals--both have a protein-lipid bilayer with abundant sterols.

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DNA Replicatoin, Ploidy, and Cytoplasmic DNA type of Prokaryotes and Eukaryotes

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1). Prokaryotes--replication by binary fission--haploid--and Plasmids
2). Eukaryotes--Mitosis--Diploid--and DNA present in mitochondria, kinetoplasts, and chloroplasts.

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Transcription and Translation in Prokaryotes vs. Eukaryotes

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1). Prokaryotes--Coupled
2). Eukaryotes--Uncoupled

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Translation

Back 67

1). Prokaryotes--first amino acid is a n-formyl Met--iniation by shine delgarno sequence--and 70S ribosomes
2). Eukaryotes--first amino acid is Meto--Initiation is by ribosome binding to 5' end of message ---80S ribosome.

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Metabolism of Prokaryotes vs. Eukaryotes

Back 68

1). Prokaryotes: A). Oxidative phosphorylation--ETC on cell membrane B). Photosynthesis--chlorophyll like components on membranes C). Energy Storage--PHB (glycogen like).
2). Eukaryotes: A). Ox. Phos--ETC in mitochondria B). Photosynthesis--chloroplasts C). Energy Storage--glycogen

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Movement

Back 69

Both prokaryotes and eukaryotes have flagella (simple in prokaryotes).
Only animal cells have amoeboid movement.

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Bacterial features not in human cells

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Capsule, outer membrane, periplasmic space, rigid cell wall, cytoplasmic membrane lacking sterols, mesosome, flagellum, fibrae (pili), 70S ribosomes, endospore, lack of nuclear membrane, plasmids, haploid chromosome

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Capsule

Back 71

1). Mainly polysacchardie (proteinaceous in Bacillus anthracic and Yersinia pestis)
2). Major Virulence Factor--allows bacteria to evade phagocytosis, adhere to host cells etc.

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Gram Positive Cell Walll

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Cell wall is a single-bag shaped structure composed of a network of repeating cross-linked peptidoglycan also called murein;
It has an N-acetyl muramic acid- N-acetyl glucosamine co polymer backbone.
Cross linkage is plentiful and occurs usually via a peptide bridge.

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Gram negative cell wall

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Much more complex (peptidoglycan layer thinner) and overlaid by an outer membrane;
Cross linkage is infrequent and results from direct chemical bonds.

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Lipoteichoic Acid

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Causes necrosis; induction of cell mitosis at the site of infection; stimulation of specific immunity; stimulation of non-specific immunity; adhesion to the human cell; complement activation; and induction of hypersensitivity

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LPS (Endotoxin)

Back 75

1). composed of o-polysaccharide, the core polysaccharide and lipid A. Lipid A is anchored in the outer membrane.
LPS induces: fever, hemorrhagic necrosis, disseminated intravascular coagulation, tumor necrosis factor, activation of the alternate complement pathway, stimulation of bone marrow cell proliferation, and enhancement of the immune and the Limulus lysate reaction

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Protoplasmic Membrane

Back 76

Encloses the cytoplasm; Plays a vital role as an osmotic barrier; is the site of initiation in cell wall synthesis; site of attachment of the chromosome; is the site of cytochrome system and the location of the various transport enzymes.
The only known role of it in pathogeneiss is that it is the source of lipoteichoic acid.

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Acid-Fast Bacteria (Envelope)

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Peptidoglycan 0.01nm (trilayer); Polypeptides, Mycolic acid, arabinogalactans, cord factor, sulfolipids, mycosides, and lipooligosaccharides

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The Gram Stain (4 Steps)

Back 78

1). Crystal Violet--all purple
2). Gram's Iodine (potassium iodide)--cells purple
3). Decolorize with alcohol--positive remain purple and negatives lose color
4). Safranin Red--Negatives become red and positives remai purple

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Acid-Fast Stain

Back 79

1). Stain wil hot carbol-fuchsin (all red)
2). Decolorize with acid-alcohol (only acid fast cells retain red)
3). Counterstain with methylene blue (acid fast cells remeain red and others are blue)

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Sporulation

Back 80

1). Spre septum begins to isolate newly replicated DNA and a small portion of cytoplasm 2). Plasma membrane starts to surround DNA, cytoplasm and membrane 3). Spre septum surrounds isolated portion forming forespore 4). Peptidoglycan layer forms between membranes 5). Spore coat forms 6). Endospore is freed from cell

Endospore is rich in dipicolinate--they cannot divide but can germinate into vegetative cells

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Koch's Postulates

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Discovered Bacillus anthracis;

1). The infecting agent must be present in every case of the disease. It must be absent in health 2). The infecting agent must be isolated from the affected host and propagated in culture 3). The agent must cause the specific disease when inocculated into a healthy host 4). The infecting agent must be isolated from the newly infected host.

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Streptococcus mutans

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Cause of smooth surface dental caries

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Oral Bacteria

Back 83

1). Supragingival--caries development
2). Subgingival--causes periodontal disease

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Attributes of a Successful Pathogen

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1). Gain entry into a host 2). Find a unique niche within the host 3). Evade, circumvent, or exploit the host's innate defense mechanisms 4). Multiply 5). Exit the host

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Strain

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Designates a group of microbes belonging to a specific species

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Bacteria

Back 86

Single celled plants; prokaryotic type

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Viruses

Back 87

Obligately, intracellular self-replicating agents; technically not cells

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Fungi

Back 88

Lower plants; can be multicellular; eukaryotic cell type

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Protozoa

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Lower animals; eukaryotic cells

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Antimicrobial Agents

Back 90

1). Antibiotics 2). Antiseptics 3). Sulfonamides

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Antiseptics

Back 91

Do NOT display selective toxicity for microbes so use is limited to topical applications.
Chlorohexidine is the most widely used in dentistry--mouthwash.

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Sulfonamides (sulpha drugs)

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Bacteriostatic Agents

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Antibiotics

Back 93

Microbiocidal agents produced by 1 microorganism and used against another.
They target various metabolic and biosynthetic pathways of bacteria

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The "Perfect" Antibiotic

Back 94

1). Selective Toxicity--only target microbes and spare the mammalian host 2). Bacteriocidal( can be bacteriostatic but not preferred) 3). Long in-vivo half life 4). Good Tissue Distribution 5). Low binding to plasma proteins 6). Oral and parenteral administration possible 7). Limited drug interactions 8). Eventually must be eliminated from patient

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Rational Antibiotic Therapy

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Antibiotics are prescribed to combat specific microbes; It takes time to diagnose and confirm; Often impractical due to severity of infection

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Empirical Antibiotic Therapy

Back 96

Use best guess ( a broad based antibiotic).
Ex: Tetracycline

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2 Methods to determine antibiotic sensitivity

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1). Dilution Test 2). Diffusion Test

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Diffusion Test

Back 98

Bacteria are allowed to grow confluency on an agar plate to form a lawn. Discs impregnanted with the antibiotic are added to the lawn. A zone of inhibition (an area of clear agarose that forms around the disc due to bacteria being killed) forms if the bacteria are sensitive to the antibiotic.

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Dilution Test

Back 99

Bacteria are initially cultured in growth media containing serially diluted concentrations of antibiotic. The cultures are then screened visually for bacterial growth. The lowest concentration of antibiotic that shows no bacterial growth is called the minimum inhibitory concentration. The cultures are then transferred to agar plates containing growth media but no antibiotic. The lowest concentration that yields no visible bacterial colonies is the minimal bacteriacidal concentration.

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Antibiotic Prophylaxis

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It is somtimes necessary to administer antibiotics before a procedure. This is to prevent the initial colonization of microbes, to prevent emergence of a latent infection, or to prevent the spread of a latent infection.
Patients who may be appropriate for this include: immunocompromised patients, patients with facial or skull fractures, and patients at risk for bacterial endocarditis.

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Infective (bacterial) Endocarditis

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Potentially fatal condition characterized by inflammation of the endocardium around the heart valves that occur when bacteria colonize abnormalities on the valve surfaces.
Could be caused by tooth extraction and periodontal therapy.

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Classes of Antimicrobial Drugs

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1). Antibacterial (Antibiotics)--cell wall synthesis inhibitors, protein synthesis inhibitors, and nucleic acid synthesis inhibitors. 2). Anti-Viral 3). Anti-Fungal

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Antibiotics that block peptidoglycan synthesis

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1). Are bacteriocidal 2). Peptidoglycan is not found in mammals so these antibiotics show high selective toxicity 3). Gram + cells have more peptidoglycan

Two classes are 1). B-lactams and 2). Glycopeptides

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Antibiotics that block peptidoglycan synthesis cont'd

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Once the cell wall integrity is compromised, the bacteria becomes osmosensitive and in a hypotonic environement water enters the cell causing it to lyse.

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B-Lactams

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1). Contain a B-lactam ring essential for antibacterial activity 2). Binds to penicillin binding proteins which are responsible for generating the crosslinks in the wall.

Ex: 1). Penicillins (Ampicillin, amoxocillin broad spectrum) and (Methicillin-narrow spectrum but insensitive to some B-lactamases
2). Cephalsporins-Cephalexin and cefotaxime--1st generation effective vs. G+ cells and newer generation effective against G- cells.

They are administered orally and intravenous.

Side Effects--Allergy

Resistance--altered PBP so that the drug can't bind.

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Augmentin for B-Lactam resistance

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B-lactamases cleave the B-lactam ring of amoxicillin and make the drug inactive. However, potassium clavulanate inhibits these enzymes.

Augmentin = amoxycillin + potassium clavulunate

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Glycopeptides

Back 107

1). Bind directly to growing peptidoglycan chain to block elongation.

Examples: 1). Vanomycin 2). Teicoplanin Both are narrow spectrum (G+ only).

Generally not administered for oral infection but can be used for prophylaxis for IE risk patients.

Side Effects--skin rashes, ototoxicity, nephrotoxicity.

Resistance-- G negative are resistant because they do not allow drugs to penetrate--aquired resistance ( alteration of NAM/NAG terminal amino acids

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Protein Synthesis Inhibitors

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1). Largest Group 2). Targets bacterial ribosomes 3). Aminoglycosides, tetracylcines, macrolides, lincosamides, chloramphenicol, and fusidic acid.

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Aminoglycosides

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1). Bind irreversibly to 30S subunit to prevent translation initiation.
2). Bacteriocidal and broad spectrum (Gram + and -)( targets bacteria that use aerobic respiration, anaerobes are resistant).

Examples: 1). Streptomycin 2). Gentomycin 3). Katamycin/Neomycin

Side Effects--Nephrotoxic (kidney damage), ototoxic (hearing loss).

Administered Topically

Resistance--reduced membrane permeability; efflux pump; enzymatic alteration of 30S to prevent drug binding.

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Tetracyclines

Back 110

1). Bind reversibly to 30S to prevent association of tRNA with ribosome. It is bacteriostatic and broad spectrum.

Examples: 1). Tetracylcline 2). Doxycline

Administration--orally, used in mouthwashes

Side Effects--GI upset, discolors teeth in children.

Resistance--High-usually lowered cell permeability, efflux pump, and altered 30S.

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Macrolides and Lincosamides

Back 111

1). Both bind reversibly to 50S subunit to prevent elongation. It blocks ribosomal translocation on the growing protein chain (macrolides) or on the peptide bond formation (lincosamides). Generally bacteriostatic but in high doses can be bacteriocidal. Broad spectrum and similar to penicillins so administered to patients with allergies to penicillin.

Examples: 1). Erythromycin (Macrolide) 2). Clindamycin (lincosamide)

Administration--Orally

Side Effects--Nausea

Resistance--Alteration of 50S

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Chloramphenicol

Back 112

Irreversibly binds 50S; broad spectrum.

Last resort--potentially fatal side effects--disrupts protein synthesis in bone marrow cells to shut down red and white blood cell production--irreversible.

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Fusidic Acid

Back 113

Blocks elongation of factor G to prevent ribosome translocation. Toxic to mammalian 80S so not available in the US.

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Inhibitors of Nucleic Acid Synthesis

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Sulfonamides and Trimethoprim

Antimetabolites--inhibit synthesis of THF (necessary for purine, amino acid synthesis).

Sulfonamides are analogs of para-aminobenzoic acid (PABA) which is a nucleotide precursor produced by the bacteria . Trimethoprim is a pyrimidine analog.
Sulfonamides inhibit dihydro ptereoate synthetase to prevent production of folic acid (DHF) and trimethoprim inhibits dihydrofolate reductase.

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Sulfonamides and Trimethoprim

Back 115

Broad Spectrum
Administered together are bacteriocidal---Co-trimoxazole

Adminstered--Orally

Side Effects--Allergy ( can not be adminstered topically for oral infections, nausea, vomiting, headaches, depression, dizziness,

Resistance--widespread. 1). alteration of target enzyme so that it binds PABA better than sulfonamide 2). some bacteria can use exogenous THF so it wont be affected

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Inhibitors of DNA Replication

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Quinilones

Inhibit DNA gyrase; bacteriocidal (low dose-bacteriostatic); Moderate spectrum; primarily effective in treating G-

Examples: 1). Nalidixic Acid 2). Ciprofloxacin

Administered--orally

Side Effects--GI Distress, rare neurotoxicity and photosensitivity

Resistance--Mutation in DNA gyrase and changes in bacteria permeability.

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Inhibitors of RNA Synthesis

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Rifamycins

Bind bacterial RNA polymerase to prevent the initiation of mRNA synthesis; Bacteriocidal; Broad spectrum and often used to treat mycobacterial infections.

Examples: 1). Rifampicin 2). Rifabutin 3). Rifampin

Administered--Orally

Side Effects--minimal (rash and jaundice)

Resistance--mutation in RNA Polymerase B subunit

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Antiviral Agents

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Virus is tough to kill because has no peptidoglycan, no ribosomes and no cell wall. The steps in the replication cycle are potential targets.
Attack only in actively replicating viruses (no latent viruses). Therefore they are only virulostatic.

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Important Viruses in Dentistry

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1). HIV (retrovirus) 2). Herpes (DNA) 3). Influenza A (RNA) 4). Hepatitis (DNA) 5). Respiratory Syncytial Virus (RNA)

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Virus Life Cycle

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1). Absorption and Penetration 2). Uncoating 3). Synthesis and Assembly of viral components 4). Release of virions from the host cell

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Anti-Virals

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1). Inhibitors of Nucleic Acid Synthesis 2). Protease Inhibitors 3). Entry and fusion inhibitors 4). Integrase Inhibitors 5). Miscellaneous

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Nucleic Acid Synthesis Inhibitors

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Inhibits nucleosides and polymerases that incorporate nucleosides into RNA and DNA. Can also block elongation.

Ayclovir (ACV)--is the first effective anti-herpes agent and has been used for 25 years.

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ACV

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Nucleoside Analogue (Guanine analogue)
Needs to be activated by a viral thymidine kinase (adds a phosphate). It is then activated by cellular enzymes to a triphosphate before it is active

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GCV (Ganciclovir)

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Guanine Analogue
It is the first effective anti-CMV drug and also active against herpes.

GCV triphosphate concentrations may be 100x greater in CMV infected cells than in uninfected cells.

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Inhibitors of Nucleic Acid Synthesis--Nucleoside Analogues

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1). Zidovudine (ZDV or AZT)

The analogue of thymidine and converted to triphosphate analogue of dTTP by cellular kinases. It inhibits HIV reverse transcriptase.

The first anti-HIV medication.

HIV can rapidly develop resistance to it.

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Inhibitors of Nucleic Acid Synthesis--Nucleoside Analogues

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1). Lamivudine (3TC) 2). Emtricitabine (FTC)

Analogues of cytosine and are converted to triphosphates analogues of dCTP by cellular kinases.
They inhibit reverse transcriptase and hepatitis B viral DNA replication.
Useful for HIV/Hepatitis B co-infection

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Inhibitors of Nucleic Acid Synthesis--Nucleoside Analogues

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1). Didanosine( ddI) 2). Zalcitabine (ddc) 3). Stavudine (d4T)

Activities similar to ZDV and inhibit HIV reverse transcriptase

They are neuropathic

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Inhibitors of Nucleic Acid Synthesis--NON Nucleoside Reverse Transcriptase Inhibitors (NNRITs)

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1). Efavirenz

Approved by FDA
Bind directly and noncompetitively to HIV reverse transcriptase and inhibit DNA polymerase activity. They cause a conformational change and disrupt the catalytic site

Emergence of resistance is rapidly when used alone.

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HIV Protease Inhibitors

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HIV Protease is required for activation of infectious HIV

1). Amprenavir 2). Atazanavir 3). Indinavir 4). Lopinavir 5). Nelfinavir 6). Ritonavir 7). Saquinavir

Peptidomimetic analogues of HIV and bind competitively to the active site of HIV Protease. They prevent the cleavage of viral polyprotein precursors and the formation of mature viruses. They are very toxic drugs and can cause cardiovascular disease, vomiting and diarrhea.

Nonpeptidic Protease Inhibitors--1). Darunavir 2). Tipranavir

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HCV Protease Inhibitor

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1). Boceprevir 2). Teloprevir

Inhibit NS3/4A and HCV serine protease which are critical for viral replication. They must be used in combination with peginterferon alfa and ribavirin.

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Entry and Fusion Inhibitors

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1). Maraviroc (Selzentry)

Approved by FDA in 2007. Blocks the chemokine receptor CCR5. It can't block the T-type virus (CXCR4 co-receptor).

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Entry and Fusion Inhibitors

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1). Enfuvirtide (T20)

A 36 amino acid synthetic peptide that disrupts the HIV-1 molecular machinary at the final stage of fusion with the target cells.
Administered by a subcutaneous injection.

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Integrase Inhibitors

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1). Raltegravir (MK-0518). 2). Isentress

First drug in this class approved by the FDA.
Targets the HIV integrase which integrates the viral genetic material into human chromosomes.
Did not result in increased serum levels of total cholesterol, LDL cholesterol or triglycerides.

Also have 2). Gilead GS-9137 and 3). NIH 118-D-24

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Highly Active Anti-Retroviral Therapy (HAART)

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Cocktail of agents (3 or 4 different drugs)

To prevent the development of drug resistance

Effective in reducing HIV plasma concentrations

Not eliminating latent proviral DNA

Since 1995 the mortality of HIV has decreased by using these protease inhibitors.

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Miscellaneous Anti-Viral Drugs

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1). Interferons--play an important role in the first line of defense. Part of the non-specific immune system and are induced at an early stage in viral infection. Made by cells in response to a stimulus and then bind to receptors and induce transcription of approx 20-30 genes and results in an anti-viral state in the target cells. Interferon alpha has been used to treat Hepatitis B and C.

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Miscellaneous Anti-Viral Drugs

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2). Ribavirin

It is activated by cellular kinases which change it into the 5'triphosphate nucleotide. It interferes with RNA metabolism related to viral replication. It has a wide spectrum of activity against many RNA and DNA viruses

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Miscellaneous Anti-Viral Drugs

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3). Amantadine

Interferes with viral production, M2 ( an ion channel) which isrequired for the virus to become uncoated. It has the narrowest spectrum and only affects Influenza A.

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Miscellaneous Anti-Viral Drugs

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4). Rimantadine

Scientists do not know why it works but believe that it inhibits influenza's replication possibly be preventing its uncoating.

Resistance to this can result by amino acid substitutions in M2 which prevent binding of the virus to the ion channel.

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Fungi

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Eukaryotic cells that lack chloroplasts. They require an aerobic environment to grow. They have a bilayered cell membrane with sterols (Ergosterol). Most anti-fungal agents work by disrupting ergosterol either by binding to it and punching holes through the fungi cell wall or by interfering with its synthesis.

They aslo have a cell wall composed mostly of carbohydrates and protein and is a potent antigen to the human immune system.

Also has a polysaccharide capsule surrounding the cell wall.

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Anti-Fungal Antibiotics

DNA Synthesis Inhibitors

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1). Flucytosine

Cytosine analog and blocks the synthesis of Fungal DNA and RNA.
Exhibits selective toxicity because it is only activated in fungal cells and not mammalian.

It is rarely used alone and is relatively non-toxic.

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Sterol Synthesis Inhibitors (Azoles)

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1). Fluconazole 2). Clotrimazole 3). Ketoconazole 4). Itraconazole 5). Voriconazole

Inhibits synthesis of ergosterol. Broad spectrum and eventually leads to death of the fungal cell.

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Sterol Binding Drugs (Polyenes)

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1). Amphotericin B 2). Nystatin

Leads to fungal cell death. It is broad spectrum and given topically or intravenously. It has severe side effects when used systemically.

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Glucan Synthesis Inhibitor (Echinocandins)

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1). Anidulafungin 2). Capsofungin 3). Micafungin

Rapidly and irreversibly inhibit glucan synthesis by inhibiting 1,3 D-glucan synthase

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Bacterial Mutation Definitions

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Genotype--genetic potential of a cell
Phenotype--measureable property produced by the genotype in cooperation with environment
Mutation - a lesion in a gene
Mutant - a cell carrying a mutation
Wild type - refers to an organism or a gene most often found in the natural setting; e.g., E. coli are Lac+

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Point Mutations

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1). Substitutions 2). Deletions 3). Insertions of a single base

Subsitution can be A). Transition--purine to purine or pyrimidine to pyrimidine B). Transverision--Purine to Pytrimidine or vice versa

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Multiple Base Mutations

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Substitutions, Deletions, Inversions, and Insertions.

Inversions are complicated because of the polarity of DNA

5'AAACCC3'
3'TTTGGG5'
to
5'GGGTTT3'
3'CCCAAA5'

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Frame-Shift Mutation

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Causes a shift in the normal reading frame of the RNA message.

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Subsitution

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Can cause a silent, missense, or nonsense mutation.

1). Silent: UAC (Tyr) to UAU (Try)
2). Missense: UAC (Tyr) to UCC (Ser)
3). Nonsense: UAC (Tyr) to UAG (stop codon)

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Molecular Basis for Mutation

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Most point mutations result from uncorrected errors in replication .

Multiple base mutations often occur by homologous or non-homologous recombination (both mediated by transposons).

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Transposons

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Genetic elements that have the ability to move-transpose-between sites on DNA by nonhomologous recombination (as opposed to homologous recominbation which occurs between two similar DNA sequences).

Occur within longer sequences of DNA (plasmids or chromosomes).

Replicate along with surrounding DNA rather than autonomously.

Transposase cuts inverted repeat sequences of DNA at each end of transposon. It also cuts other DNA often at random sites.

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Transposition

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Results in an insertion mutation.
It can be replicative--1). a transposon copy is created at new site 2). "copy and paste" 3). Multiple copies per cell

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Mutations caused by Transposition

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Indirect through homologous recombination (a single crossover) between repeated copies of a transposon: 1). Deletion 2). Inversions 3). CAn also occur with repetitive sequences

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Selective Pressure

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Selection--a condition in which only bacteria with a certain phenotype are recovered. Example: addition of ampicillin to growth media selects for cells that are resistant to ampicillin by killing those that are sensitive.

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The Fluctuation Test

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Employs resistance to phage infection as a marker
Addresses the question: Does exposure to a selective agent induce mutations at the time of exposure or merely select for cells possessing pre-existing mutations?

If bacteria sense the bacteriophage on the plates and then a certain percentage of the bacteria can mutate to resistance in response, the frequency of bacteria that survive to form colonies should be about the same on each plate, as in this picture.

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The Replica Plating Test

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Employs resistance to streptomycin as a marker.
Addresses the question: Does exposure to a selective agent induce mutations at the time of exposure or merely select for cells possessing pre-existing mutations?

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Baceterial Mutation relationship to Selection

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Cells possessing pre-existing mutations that are beneficial in a given environment will survive and replace cells that are less fit.

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Plasmids

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Autonomously replicating nucleic acid molecules which are distinct from the chromosome and do not encode essential functions.
Range from a few kilobase pairs to several hundered kilobase pairs.

Carry a few to hundreds of genes. (Chromosomes range in size from 0.5-1.0Megabp and average 1 gene/kilobase).

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Plasmids Cont'd

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Both Plasmids and chromosomes are circular and supercoiled in most bacteria (linear in some species).

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Plasmid Copy Number

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Number of plasmids per chromosome or per cell. Generally 2 classes: 1). Low copy #: F, etc. present at 1-2/cell
2). High: Smaller plasmids (lessthan 10kb) and 40 or more copies/cel.

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Plasmids Cont'd

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Partition mechanisms help insure that a plasmid is distributed to each daughter cell during cell division.
May be functionally analogous to centromeres in eucaryotes.
Help maintain stability of plasmid in population, even when there is no selective pressure.

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Plasmids Cont'd

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Other plasmid stability mechanisms: Poison/antidote
Plasmid produces stable poison, unstable antidote
If plasmid is lost, poison will kill cell

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Plasmids Cont'd

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1). "Selfish" DNA--Selection at the level of DNA not just the bacterium. (Poison System)
2). Can also increase fitness of cell
3). Encode accessory traits

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Plasmid Encoded Traits

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Conjugation (R plasmids),
Resistance to antibiotics (Many bacteria),
Resistance to heavy metals (Many bacteria),
Bacteriocin production (e.g., E. coli),
Substrate catabolism, e.g.:
Pseudomonas spp.
Chakrabarty’s “multi-plasmid hydrocarbon-degrading Pseudomonas” --Supreme Court, 1980

Also encode virulence factors (eg Bacillus Anthracis, E. coli)

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Plasmid Use by Scientists

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1). Recominbant DNA/Molecular cloning 2). Isolate and overproduce DNA for recombinant proteins

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Recombinant Protein Production

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1). Introduce plasmid by transformation 2). Isolate cells with plasmids 3). Induce protein production 4). Isolate protein

Therapeutics: Insulin
Vaccines: Lyme Disease, HepB, HPV (Gardacil)

Before recominant DNA the source of insulin were cadavers and animal pancreas which both posed allergenic risks.

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Plasmid Use for DNA Vaccines

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1). Introduce plasmid by transformation 2). Isolate cells with plasmid 3). Isolate DNA

Influenza, Birdflu, H1N1

Also plasmids are used for gene therapy

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Bacterial Conjugation

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Transfer of DNA from a donor to a recipient cell
Requires cell-to-cell contact
Requires conjugative genes in donor, usually on a plasmid.
Can also occur with plasmid integrated into chromosome
Widespread: Gram negatives and positives

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E. coli F plasmid model

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Conjugation is promoted by self-transmissable plasmids: 1). F "fertility" factor and 2). R "resistance" factor

Donor passes F to Recipient.
The donor must produce: 1). Pili 2). Nicking activity 3). DNA transfer machinery

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Conjugal transfer of F

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1). F-encoded endonucleases make a single strand cut at oriT site on F. 2). DNA strand passes into recipient cell 3). Complementary strand is made in both cells 4). The cytoplasmic bridge breaks down and two cells separate and both are now F+ donors.

Experiment: If you mix F+ cells with F- cells you will get F+ cells.

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Hfr Formation

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F can integrate into chromosomes.
Occurs by a single cross-over between homologous sequences on F and the chromosome.

Hfr--Confer a High Frequency of Recombination for bacterial genes.

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Hfr Transfer

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1). Requires prior Hfr formation 2). Genes can then be transferred from the Hfr donor to an F- recipient. 3). Genes are transferred in a regular order 4). Donor tra operon enter last 5). Very few recipients become donors because this requires transfer of the entire chromosome; transfer is spontaneously interrupted.

Experiment: Mix Hfr and F- and you get recombinant F- recipients.

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F' Formation

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1). Integrated F can excise a). Clean excision--returns to life as F b). pick up adjacent chromosomal genes--called F'--transferred like F

Experiment: Mix F' and F- and get F' recipients.

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Mobilization

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Mobilizable plasmids are hitchhikers that are transferred from one cell to another through the action of conjugative plasmids
Conjugation machinery encoded by another plasmid acts on the oriT region of the mobilizable plasmid to effect transfer

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Transformation

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The uptake and incorporation of free DNA from the environment.
It is taken up by genetically competent cells.
The source of DNA is from lysed bacterial cells. The DNA can be of two types:
1). Plasmid DNA--must be able to replicate in recipient
2). Chromosomal DNA--must integrate into the chromosome, have homology to recipient genome, and enter as fragements due to its large size.

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Griffith Experiment

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Have Rough, Smooth, and Heated Smooth Cells. Smooth cells are virulent because they have capsules.
1). Rough--mice lived 2). Smooth--mice died
3). Heated smooth--mice lived.
4). Rough+Heated smooth--mice die--but smooth cells can be recovered from mice.

Suggested that bacteria are capable of transferring genetic information through transformation. DNA encoding the capsule was transferred.

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Transformation Cont'd

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Occurs naturally in Neissara, Haemophilus (Gm-), Streptococcus, and Bacillus (Gram+).
Can be induced in others such as E. coli
Cells must be competent

Cell contact is not necessary--supernatant or filtrate will work. Supernatant only contains DNA.

Transformation can be blocked by addition of DNAase.

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Transduction

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It is a viral-mediated genetic exchange. It occurs widely in Gram positive and gram negative bacteria.

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Lysogenic Conversion

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Lytic pathway--virus takes over cells reproduction and protein synthesis and cell becomes lysed.
Lysogenic pathway--can give rise to lytic pathway (needs to be induced such as messing with the DNA)

Lysogenic phage carries genes that:
confer new properties on the host
are normal constituents of the phage genome (not chromosomal genes)

Examples: 1). b-phage of Corynebacterium diphtheriae
--Carries the diphtheria toxin gene
Conversion is from non-toxigenicity to toxin production
2). CTXphi phage of Vibrio cholerae
Carries the cholera toxin gene
Conversion is from non-toxigenicity to toxin production
3). 8232.1 phage of Streptococcus pyogenes
Carries a number of superantigen genes
Conversion is to superantigen production

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Generalized Transduction

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1). Results from errors during packaging 2). Can involve chromosomal genes, plasmids, other phages 3). Requires that the phage assembly occur by "head full" mechanism

Cell contact is not necessary--cell filtrate or supernatant will work.

DNAase treatment has no effect

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Horizontal Transfer

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Transfer of genes coding for antibiotic resistance possible or virulence factors between genus, species, sexes etc.
1). Conjugation--Resistance plasmids 2). Transformation--Abx^r
3). Transduction--any chromosomal trait --related case: pathogenecity islands in Staphylococcus aureus

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Antibiotic Resistance in Bacteria

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1). "Natural Resistance"--lack of a sensitive target (Distinct DNA gyrase of Borrelia is poorly sensitive to quinones)--natural resistance to penetration or accumulation of drug (Psuedomonas, Acinetobacter)--Mutations in chromosomal genes that prevent antibiotic action (may compromise bacterial cell, critical function may be altered, and antibiotic resistance is at the expense of normal cellular activities).

Natural resistance is usally stable over time and not easily spread.

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Antibiotic Resistance in Bacteria

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2). Aquired Resitance

Prevalent in Clinical Setting, Novel genes that confer resistance various means, and genes are usually carried by plasmids or transposons which facilitates spread

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Modes of Resistance

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Usually found on R-plasmid or transposon

Enzymatic destruction of antibiotic
Enzymatic modification of antibiotic leading to decreased drug toxicity
Active export of antibiotic from cell
Modification of antibiotic target site
Cell provided with bypass mechanism not susceptible to antibiotic inhibition

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Modes of Resistance

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Usually found on chromsomes:

mutations in chromosomal genes that change proteins (usually by a single amino acid, though multiple changes can occur).
often alters a drug target to prevent drug binding, while still allowing the protein to perform its normal function

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Penicillin and B-lactam Resistance

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Non B-lactamase resistance:
1). New penicillin-binding protein: methicillin resistance in S. aureus, acquired chromosomal gene called mecA, termed methicillin resistance or MRSA

mecA encodes a new PBP that doesn't bind any of the B-lactams so it is able to synthesize cell wall

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Aminoglycosides Resistance

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Enzymatic alteration to detoxify the drug or prevent uptake--adenylase, phosphotransferase, acetyl transferase. The altered drug has decreased affinity for ribosome and transport into the cell is reduced.

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Chloramphenicol Resistance

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Detoxification of drug by acetylation of hydroxyl groups by chloramphenicol transacetylase
Interference with uptake

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Tetracycline Resistance

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Primarily alteration of drug uptake--efflux.

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Macrolides and Lincosamides Resistance

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Enzymatic modification (methylation) of 23S ribosomal RNA of sensitive cells converts ribosome to drug resistance (unable to bind inhibitor)

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Glycopeptides (Vancomycin) Resistance

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Presence of a new cell wall synthesizing enzyme (D-ala: D-ser or D-ala:D-lac ligase) which creates a cell wall with reduced affinity for glycopeptide antibiotics (gram +).

D-ala-D-lac wont bind vancomycin.

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Sulfonamides Resistance

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Drug-resistant dihydropeteroate synthase (bypass mechanism)
Can be taken up on R plasmids or result from acquisition of a mutant chromosomal gene by transformation.

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Trimethoprim Resistance

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Drug resistant dihydrofolate reductase (bypass mechanism)
Can be taken up on R plasmids or result from acquisition of a mutant chromosomal gene by transformation.

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Trimethoprim + Sulfonamide

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1). TMP-SMX 2). Septra 3). Bactrim

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Heavy Metals Resistance

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Enzymatic reduction of heavy metal salts to metallic state and vaporization

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Antibiotic Resistance with Chromosomal Mutations

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1). Rifampin--Single base mutations in the beta subunit gene of RNA Polymerase
2). Quinilones (Nalidixic Acid)--Single base mutations in the DNA gyrase alpha subunit
3). Penicillin--mutations in PSP genes.

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Spread of Antibiotic Resistance

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1). Conjugation 2). Transformation 3). Selective Pressure 4). Transduction 5). Transposition--natural genetic engineering

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Transposition + Gene Transfer

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1). Exchange and rapid dissemination of antibiotic resistance, and other favorable traits
2). Also results in gene reassortment--new combination of genes, plasmids possessing multiple resistance genes, sometimes get resistance determinants that you don't select for

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The ESKAPE pathogens--problems in hospitals with resistance

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Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumanii
Pseudomonas aeruginosa
Enterobacter species

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Recent Problems with antibiotic resistnace

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Tuberculosis
Malaria
methicilin resistant Staphylococcus aureus (MRSA)
Streptococcus pneumoniae
Gonnorhea (Neisseria)
Typhoid fever
Vancomycin/glycopeptide intermediate Staphylococcis aureus (VISA/GISA)
Vancomycin resistant enterococci (VRE)

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Health-Care Infections in the US

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4th leading cause of infection in the US
Infections have increased

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Zeitgeist of Antibiotic Resistance

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Usually the resistance mutations do not compromise the fitness of the host so the microorganism can grow as well as the parental one

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General dealing with antimicrobial resistance

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1). Surveillance 2). Prevention and Control 3). Research 4). Product Development

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Preventing Antibiotics Resistance in Clinical Setting

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Approx 50 years for bacteria to learn to deal with antibiotics

1). Prevent infection 2). Diagnose and treat infection 3). Use antimicrobials wisely 4). Prevent transmission of infection

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Purines vs. Pyrimidines

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Purines--Guanine and Adenine (Ag is pure)

Pyrimidines--Cytosine and Thymine