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81 Cards in this Set

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  • Back
What are 3 inhibitors of bacterial cell physiology that are especially good because their targets are UNIQUE to microbes?
1. Cell wall inhibitors
2. Translation inhibitors
3. Metabolic analogues
What are 3 inhibitors of cell physiology with little selectivity between proks/euks?
-Cell membrane inhibitors
-DNA synthesis inhibitors
-Transcription inhibitors
What is the added benefit of using Metabolic analogue inhibitors as antimicrobials?
They can be targeted to specific microbes
What are the 3 main mechanisms for bacterial resistance to antibiotics?
1. Antibiotic efflux pumps
2. Modification of the antibiotic
3. Destruction of the antibiotic
What antibiotic is resisted by antibiotic efflux pumps?
What antibiotic is resisted by covalent modification?
What antibiotic is resisted by destruction?
What is an antiseptic applied to and how does it work?
-Applied to the skin
-Reduces # of bacteria
What is a Disinfectant applied to and how does it work?
-Applied to an inanimate object
-Kills most bacteria
How do most antiseptics and disinfectants act?
Nonspecifically - no differentiation between proks and euks
What was Triclosan originally intended for?
Preventing bacterial degradation of plastics
What happened after a marketing genius put triclosan into hand soap?
Triclosan resistant bacteria evolved so now it can't be used to preserve plastics anymore.
Who discovered Penicillin?
Alexander Fleming
What are 2 main types of antibiotics based on how they're generated?
What ARE antibiotics?
Low MW chemicals produced by microbes that inhibit the growth of other microbes.
What is the problem encountered in many of the antibiotics that have been isolated?
They are nonselective in their toxicity, and damage the host as well as the target pathogen.
What are 2 fungi and 3 bacteria that produce useful antibiotics?
Penicillium and Cephalosporium
Streptomyces, Bacillus, and Microspora
What is the ideal property of an antimicrobial agent?
Selective toxicity
What allows antimicrobials to selectively kill their targets?
-Target is absent in the host
-Target has different properties than the host
What target is ABSENT in euks?
What target is DIFFERENT in euks?
Absent: the cell wall

Different: ribosomes
What are the 2 main classes of antimicrobials?
How do bacteriostatic antimicrobials work?
By inhibiting growth, but relying on the host defense mechanisms to eliminate the pathogen.
What is an example of a bacteriostatic antimicrobial?
How do bactericidal antimicrobials work? What is an example?
By directly killing the pathogen. Penicillin
What type of antimicrobial must be used in immunocompromised hosts?
What is the preferred class of antimicrobials in general?
What are 4 adverse effects of antimicrobials?
-Toxic side effects
-Development of hypersensitivity
-Masking infection without eliminating the pathogen
-Alteration of normal flora
What are toxic side effects of:
Tet: tooth discoloration
Strep: auditory damage
Chlor: anemia
What antibiotic can cause an anaphylatic shock hypersensitivity reaction to occur?
How does penicillin cause hypersensitivity?
By spontaneously hydrolyzing into penicilloic acid and conjugating to host proteins, stimulating specific antibody
Is c. difficuile normal flora?
Yes; but it's kept in low numbers by the other normal flora in the intestines.
What disease results when antibiotics kill off the normal flora in the gut?
Pseudomembranous (antibiotic associated) colitis
What drugs especially cause pseudomembranous colitis?
-Antineoplastic drugs
What drugs are used to treat C. diff infection?
Vancomycin or metranidazole
What are the 2 measurements done to establish the sensitivity of a pathogen to an antimicrobial?
1. MIC - minimum inhibitory conc
2. MLC/MBC - bactericidal
What is the minimum inhibitory concentration?
The lowest concentration of a drug that inhibits growth of the microbe.
What is the minimum lethal concentration?
-lowest concentration of drug -that kills a defined proportion of a microbial population
-at a given time
What 2 issues must be dealt with in order to achieve an effective level of antimicrobial in host?
1. Solubility/degradation
2. Half-life/clearance
What is the strategy of giving antimicrobials in small, frequent doses?
Keeping the drug concentration just a little bit above the MIC, boosting it back up everytime the drug decays.
What is the strategy of giving antimicrobials in single or dual doses?
Giving a large bolus of drug and relying on the decay time to kill the majority of the pathogen, so that patient compliance isn't such an issue.
How do we measure antimicrobial sensitivity?
Using the disk assay
What is the most useful class of antibacterial drugs?
Cell wall inhibitors
What are the 8 cell wall inhibitors?
What 3 drugs target protein synthesis?
What 4 drugs target protein synthesis?
What are the 4 drugs that are antimetabolites?
-Para-aminosalicylic acid
What are the 2 drugs that target DNA replication?
What are the 2 drugs that target RNA synthesis?
What are the 2 important functions of the bacterial cell wall?
-Protection against osmotic and mechanical shock
-Assimilation of low MW compounds for metabolism
How is it that cell wall inhibitors have high specifitiy for the pathogen and low toxicity to the host?
The cell wall is unique to prokaryotes
Where are cell wall inhibitors most useful in the growth curve?
During the logarithmic growth phase
Review; what are the 2 main components of the gram neg cell envelope?
-Inner cell membrane
-Outer cell membrane
-Periplasmic space in between with a layer of peptidoglycan in it.
What is the outer cell membrane structure?
Assymetrical with a phospholipid layer on the inner leaflet and LPS on the top; some porins intermixed.
What feature of the cell envelope is the focus of the cell wall inhibitors?
The layer of peptidoglycan in the periplasmic space.
What are the 2 things that the C-amino acid in the pentapeptide chain of peptidoglycan can be?
-Meso-Diaminopimelic Acid
What is the C-amino acid crosslinked to? By what?
-To D-ala, the D-amino acid on another pentapeptide chain
-Via a peptide bridge
What are the 3 main steps of peptidoglycan synthesis? Where does each occur?
1. Synthesis of precursors - in the cytoplasm
2. Transport of disaccharide subunits to the inner membrane
3. Assembly and crosslinking outside
What is the site of action of the beta-lactam antimicrobials?
Crosslinking of the peptidoglycan polymers in the periplasm.
What are the 2 enzymes that do the crosslinking?
What are the 4 class of B-lactam antibiotics?
1. Penicillin
2. Cephalosporin
3. Carbapenem
4. Monobactam
What do all 4 classes of B-lactams have in common?
A beta lactam ring
What is the basic structure of Penicillin?
-Lactam ring made up of cysteine and valine condensed
-Fused to a 5 member thiazolidine ring
What is the C-N bond WITHIN the beta lactam ring the site for?
Hydrolysis by Beta-lactamases to convert it to inactive penicilloic acid
What is the C-N bond OUTSIDE of the beta ring the site for?
Amidase cleavage to convert penicillin to synthetic derivatives and create other classes of antibiotics
What are 3 things that we can change by changing the R group on the B-lactam ring?
-Acid LABILITY (half life)
-B-lactamase SENSITIVITY
-Spectrum of ACTIVITY - directed at gram negs versus gram pos
What is Penicillin G?
Penicillin with a BENZYL group as its R group
-Acid labile (cant take orally)
-Sensitive to b-lactamase
-low gram neg activity
What is an antibiotic that chemists cooked up but is of no use to inhibit microbes?
Clavulanic acid
How does Clavulanic acid work when given alone?
As a covalent inhibitor of Beta-lactamase enzymes produced by microbes
When is taking Clavulanic acid good?
When given WITH penicillin that is sensitive to beta-lactamase, to prevent the inactivation of penicillin.
What is the good effect then of Clavulanic acid?
Extended utility (T1/2) of penicillin and beta-lactamase sensitive beta lactams (Solbactam)
What is the B-lactam derivitive + Clavulanic acid compound called?
What is the mechanism for peptide bond formation between the polysaccharide chains of Peptidoglycan?
A 2-enzyme reaction:
1. Carboxypeptidase
2. Transpeptidase
What are the enzymes that achieve peptide crosslinking?
1. Carboxypeptidase
2. Transpeptidase
What does carboxypeptidase do?
Cleaves the terminal D-alanine on the pentapeptide
What does transamidase do?
Forms the peptide bond between the 4th D-ala of the bridging peptide and the 3rd basic amino acid on an adjacent tetrapeptide
What are the 2 transpeptidation enzymes commonly called? Why?
Penicillin binding proteins (PBPs) - because penicillin stably binds them and inactivates the enzymes.
What is the result of penicillin deactivating the transpeptidation enzymes (PBPs)?
No cell wall --> cell death
What are the 3 mechanisms of resistance to Penicillins?
1. Decreased permeability to the drug
2. Mutations in PBPs
3. Acquisition of new DNA for b-lactamases to inactivate the drug
How can microbes decrease their permeability to penicillin?
By mutations in outer membrane proteins like PORINS
What bacteria can mutate its PBPs?
Strep pneumo
What is the primary mechanism for acquiring resistance to penicillin?
Transfer of new DNA which encodes B-lactamases; transfer is via plasmids or conjugation.