Dmp_712 Bact Exam_1 Chemotherapeutic Agents Section 6 Robertson

Front 1

Chemotherapeutic agent defn:

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Chemotherapeutic agent defn: a chemical that interferes with the growth of microbes at cocentrations the host can tolerate

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Chemotherapeutic agent
must exhibit:
with food animals concerns about:

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Chemotherapeutic agent
must exhibit: selective toxicity - exploit metabolic differences between host and parasite
with food animals concerns about: residues

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Antibiotic defn:

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Antibiotic defn: small molecules produced by living microbes that inhibit growth of bacteria

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Effectiveness of drug depends on: (4)

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Effectiveness of drug depends on: (4)
1) growth rate of parasite
2) distribution in tissues/fluids
3) Intracellular or extracellular parasite?
-extracellular - growth outside of cells
-intracellular - growth within phagocytic cells or epithelial cells
4) Non-specific binding to tissues, blood proteins and lipids

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Extracellular parasite defn:

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Extracellular parasite defn: growth outside of host cells

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Intracellular parasite defn:

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Intracellular parasite defn: growth within phagocytic cells or epithelial cells

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Desirable properties of Chemotherapeutic Agents (6)

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Desirable properties of Chemotherapeutic Agents (6)
1) Exhibit selective toxicity
2) not be allergenic
3) remain active in tissues, body fluids and inflammatory exudates (pus)
4) susceptible microbes do not develop resistance at a high rate
5) water soluble
6) rapidly reach inhibitory levels and remain

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Mechanisms of Bacterial Drug Resistance (3)

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Mechanisms of Bacterial Drug Resistance (3)
1) Change membrane composition (IM and/or OM) - reduce drug permeability
2) Enzymatic modification of drug (genes are often on plasmids)
- hydrolysis of ring structure or functional group
- incorporation of new functional group
3) change enzyme active site or sites on ribosomes involved in protein synthesis

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Mechanisms of Action of Chemotherapeutic Agents (5)
highest to lowest selective toxicity

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Mechanisms of Action of Chemotherapeutic Agents (5)
1) inhibit formation of crosslinks in peptidoglycan layer of procaryotes
2) Inhibit protein synthesis
3) Inhibit specific enzymes involved in biosynthetic pathways
4) Disrupt membrane function
5) Inhibit DNA synthesis/function

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit formation of crosslinks in peptidoglycan layer of procaryotes
level of selective toxicity?
bacteriostatic or bacteriocidal?
examples (2)?

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit formation of crosslinks in peptidoglycan layer of procaryotes
level of selective toxicity? highest
bacteriostatic or bacteriocidal? bacteriosidal
examples (2)? penicillins and cephlosporins

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit protein synthesis
level of selective toxicity?
sites of action?
bacteriostatic or bacteriocidal?

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit protein synthesis
level of selective toxicity? 2nd highest
sites of action? some 30S ribosome, some 50S ribosome
bacteriostatic or bacteriocidal? depends on class of cpds

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit specific enzymes involved in biosynthetic pathways
mechanism?
bacteriostatic or bacteriocidal?
example?

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit specific enzymes involved in biosynthetic pathways
mechanism? competitive inhibitor
bacteriostatic or bacteriocidal? bacteriostatic
example? sulfa drugs

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Mechanisms of Action of Chemotherapeutic Agents
Disrupt Membrane Function
selective toxicity due to?
used in?
example?

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Mechanisms of Action of Chemotherapeutic Agents
Disrupt Membrane Function
selective toxicity due to? limited (4th) due to similar membrane structures
used in? topical ointments
example? polmyxin B

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit DNA synthesis/function
selective toxicity level?

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Mechanisms of Action of Chemotherapeutic Agents
Inhibit DNA synthesis/function
selective toxicity level? lowest, w/exceptions

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Penicillin Important Structures (3) and their significance

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Penicillin Important Structures (3) and their significance
1) Beta lactam ring - responsible for key properties of all penicilins - reaction occurs here
2) thiazolidine ring - make antibodies to the hapten made by this ring when Beta lactam ring breaks
3) R group - modified to make different types of penicillin

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Properties of Penicillin G
History:
R group:
Active against:
Limitations:

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Properties of Penicillin G
History: first antibiotic isolated from culture
R group: benzyl group
Active against: mostly G+
Limitations: inactivated by low pH and penicillinases, high incidence of allergic reactions

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Properties of Penicillin Derivatives
Methicillin
Resistant to:
Effectiveness:

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Properties of Penicillin Derivatives
Methicillin
Resistant to: penicillinases
Effectiveness: less effective against Gm+ bacteria than penicillin G+, not used for G-

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Properties of Penicillin Derivatives
Ampicillin
Pros(2):
Effectiveness:

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Properties of Penicillin Derivatives
Ampicillin
Pros(2): stable at low pH, can be given orally
Effectiveness: against G-

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Penicillin vs. Cephlasporin (structure difference)

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Penicillin vs. Cephlasporin (structure difference)
5 membered Thiazolidine ring vs.
6 membered Dihydrothiazine ring
same R groups, same Beta lactam ring

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Mechanism of Cephalosporin

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Mechanism of Cephalosporin: same as penicillin

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R1 and R2 Groups of Cephlasporins
location:
importance:

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R1 and R2 Groups of Cephlasporins
location: R1 = R group of penicillin off Beta lactam ring, R2 off 6 membered ring
importance: different structures lead to different generations

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Penicillin
Mode of Action:

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Penicillin
Mode of Action:
Inhibit formation of cross-link (transpeptidation) in peptidoglycan
D-Ala-D-Ala peptide bond broken and D-Ala-Gly (g) formed

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Penicillin (summary)
2 most important points
R group determines:
What must be happening for drug to work?

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Penicillin
2 most important points
R group determines: stability to acid and penicillinases
What must be happening for drug to work? Cells must be growing

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Cephlasporin (summary)
Generations 1-4, benefits and limitations

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Cephlasporin (summary)
Generations 1-4, benefits and limitations
1) limited against G-
2) Greater G- spectrum, more resistant to Beta-lactamases, penetrate blood brain barrier
3) broader spectrum G-
4) Broader spectrum
(overall, broader spectrum)

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Formation of Peptide Bond (4 steps)

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Formation of Peptide Bond (4 steps)
1) peptidyl t-RNA bound to P site
2) "new" AA-t-RNA binds to A site
3) Peptide bond is formed
4) Growing peptide is moved to P site

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Inhibitors of Protein Synthesis
Streptomycin
binds:
bacteriocidal/bacteriostatic?
effective against:
Member of what family:

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Inhibitors of Protein Synthesis
Streptomycin
binds: 30S ribosome
bacteriocidal/bacteriostatic? bacteriocidal
effective against: broad G+ and G- and M. tuberculosis
Member of what family: aminoglycosidases

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Inhibitors of Protein Synthesis
Streptomycin
2 Mechanisms of action:

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Inhibitors of Protein Synthesis
Streptomycin
2 Mechanisms of action:
1) Primary: misreading effect due to distortion after binding at or near A site
2) Secondary: bind to free ribosomes, initiation complex formation is blocked

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Inhibitors of Protein Synthesis
Streptomycin
Limitations (4):

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Inhibitors of Protein Synthesis
Streptomycin
Limitations (4):
1) high resistance
2) errors may not be lethal
3) binding to ribosomes can be altered by mutation
4) Toxic to 8th cranial nerve - hearing and balance

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Inhibitors of Protein Synthesis
Tetracyclines
binds:
structure:
inhibits:
limitations (3):

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Inhibitors of Protein Synthesis
Tetracyclines
binds: 30S ribosome
structure: 4 6 membered rings
inhibits: binding of AA-t-RNA at A site
limitations (3):
1) bacteriostatic
2) nephrotoxicity & alteration of GI flora
3) Teeth & bones of developing animals turn yellow and enamel may soften

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Inhibitors of Protein Synthesis
Erythromycin
binds:
mechanism:
Limitations:

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Inhibitors of Protein Synthesis
Erythromycin
binds: 50S ribosome
mechanism: Blocks P site and inhibits peptidyl transfer by EF-1 and translocation (step 4 in peptide bond formation)
Limitations: may cause colitis in horses, guinea pigs and hamsters due to removal of normal flora

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Inhibitors of Protein Synthesis
Chloroamphenicol
Binds:
Mechanism:
Side Effect:

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Inhibitors of Protein Synthesis
Chloroamphenicol
Binds: 50S ribosome
Mechanism: inhibits peptidyl transferase (step 3)
Side Effect: aplastic anemia - no WBCs or RBCs

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Inhibitors of Protein Synthesis
Forfenicol
Used for:
Brand:
Benefit vs Chloroamphenicol:

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Inhibitors of Protein Synthesis
Forfenicol
Used for: BRD and foot rot
Brand: Nuflor
Benefit vs Chloroamphenicol: doesn't cause aplastic anemia

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Inhibition by Metabolic Analogues
Sulfa Drugs
Competitive Inhibitor of:
Slective toxicity against:
Limitations:
synergistic drug:

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Inhibition by Metabolic Analogues
Sulfa Drugs
Competitive Inhibitor of: condensing enzyme that links pteridine, PABA and glutamic acid in folic acid biosynthetic pathway (sulfa drugs are analogs of PABA)
Slective toxicity against: bacteria that make own folic acid --> very good
synergistic drug: Trimethoprim eg Tribrissen
Limitations: bacteriostatic, can induce aplastic anemia, innefective in inflammatory exudates and in sites of tissue damage

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Generally Sulfa Drugs
Analogs of:
Inhibit:
Trimethoprim inhibits:

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Generally Sulfa Drugs
Analogs of: PABA
Inhibit: synthesis of folic acid (1st step)
Trimethoprim inhibits: 4th step

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Inhibitors of Membrane Function
Types & function (2)

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Inhibitors of Membrane Function
Types & function (2)
1) Cyclic polypeptides - disrupt CM function
2) Bacitracin - polypeptide antibiotic

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Inhibitors of Membrane Function
Cyclic Polypeptides
Functional domains (2):

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Inhibitors of Membrane Function
Cyclic Polypeptides
Functional domains (2):
1) amino acids with positive charged side chains
2) hydrophobic amino acids - ipid soluble

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Inhibitors of Membrane Function
Cyclic Polypeptides
Example: Polymyxin B and Colistin (polymyxin E)
action:
bacteriocidal/static:
restriction:
Most effective against:

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Inhibitors of Membrane Function
Cyclic Polypeptides
Example: Polymyxin B and Colistin (polymyxin E)
action: disrupt cell membranes like detergents
bacteriocidal/static: bacteriocidal but no selective toxicity
restriction: use in topical ointments
Most effective against: G-

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Inhibitors of Membrane Function
Cyclic polypeptides
Polymyxin B structure (2 important components)

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Inhibitors of Membrane Function
Cyclic polypeptides
Polymyxin B structure (2 important components)
1) 4 Positive charges on ring - hydrophilic
2) hydrophobic tail

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Inhibitors of Membrane Function
Bacitracin
Location and mechanism:
Active aginst:
Limitation:

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Inhibitors of Membrane Function
Bacitracin
Location and mechanism: acts at cell membrane - inhibits movement of lipid precursors into peptidoglycan layer
Active aginst: bactericidal with activity against G+ esp Staph
Limitation: nephrtoxicity internally, restricted to topical

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Inhibitors of Nucleic Acid Synthesis/Function
selective toxicity:

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Inhibitors of Nucleic Acid Synthesis/Function
selective toxicity: very limited

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Inhibitors of Nucleic Acid Synthesis/Function
Mitomycin C
mechanism:

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Inhibitors of Nucleic Acid Synthesis/Function
Mitomycin C
mechanism: inserts into DNA helix and acts like a pin that keeps DNA strands from unwinding

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Inhibitors of Nucleic Acid Synthesis/Function
Actinomycin D
mechanism:

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Inhibitors of Nucleic Acid Synthesis/Function
Actinomycin D
mechanism: binds to GC pairs - prevents unwinding to DNA past swivel point

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Inhibitors of Nucleic Acid Synthesis/Function
Nalidixic acid
mechanism:
treats:
effective against:

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Inhibitors of Nucleic Acid Synthesis/Function
Nalidixic acid
mechanism: inhibits DNA gyrase - blocks DNA replicatoin
treats: urinary tract infections
effective against: G-

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Inhibitors of Nucleic Acid Synthesis/Function
Fluoroquinolones
examples (2):
mechanism:
activity:
bactericidal/static:

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Inhibitors of Nucleic Acid Synthesis/Function
Fluoroquinolones
examples (2): enrofloxacin (Baytril), ciprofloxacin
mechanism: inhibits DNA gyrase - prevents uncoiling
activity: wide range against G+ and G-
bactericidal/static: bactericidal at low concentrations

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Inhibitors of Nucleic Acid Synthesis/Function
Rifampicin/rifampin
mechanism:
activity:

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Inhibitors of Nucleic Acid Synthesis/Function
Rifampicin/rifampin
mechanism: specific inhibitor of DNA-dependent RNA polymerase by bindingto enzyme and blocking binding to DNA
activity: aginst wide range G+ and G- and M. tuberculosis

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For Effective Treatment 5 Factors:

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For Effective Treatment 5 Factors:
1) Begin treatment as soon as possible
2) Bactericidal drugs do not work well in large open body cavities
3) Treatment may buy time for immune response
4) Use lowest possible to limit superinfection
5) Avoid combinations of drugs if possible

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Mechanisms of Drug Resistance (4)

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Mechanisms of Drug Resistance (4)
1) Change in target of drug
2) Changes in membrane permeability
3) Production of drug inactivating enzymes
4) Selection for development of resistance

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Mechanisms of Drug Resistance
Change in target of drug
examples (2):

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Mechanisms of Drug Resistance
Change in target of drug
examples (2):
1) change at active site of beta-lactamases
2) altered DNA gyrase & quinolones

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Mechanisms of Drug Resistance
Changes in membrane permeability
Routes (2):
Bacteria & parts:

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Mechanisms of Drug Resistance
Changes in membrane permeability
Routes (2):
1) decreased capacity to keep drug out
2) increased export of drug from cytoplasm
Bacteria & parts: G-, may involve IM and OM

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Mechanisms of Drug Resistance
Production of drug inactivating enzymes
encoded by:
examples (2):

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Mechanisms of Drug Resistance
Production of drug inactivating enzymes
encoded by: plasmids usually
examples (2):
1) penicillins - beta-lactamases
2) Aminoglycosides-transferases that phosphorylate OH groups and acetylate OH and NH2 groups

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Mechanisms of Drug Resistance
Selection for development of resistance
what drug levels cause:
each generation causes:
prevent by using: bactericidal /bacterstatic?
use what age drug?

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Mechanisms of Drug Resistance
Selection for development of resistance
what drug levels cause: sub-inhibitory levels favor selection
each generation causes: increased probability of selection for mutant
prevent by using: bactericidal /bacterstatic? bactericidal drug whenever possible
use what age drug? oldest drug on market that works

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Dosage and Antibiotic Therapy
Use what dosage? why?
Avoid what term? why?

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Dosage and Antibiotic Therapy
Use what dosage? why? smallest effective dose to avoid superinfection rate
Avoid what term? why? long term therapy favors slection of drug-resistant strains

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Combination therapy
useful:
prevents:
effects:

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Combination therapy
useful: in some circumstances
prevents: selection for drug resistance
effects: additive effects

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Drug Combinations
Two bacteriostatic drugs:

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Drug Combinations
Two bacteriostatic drugs:
effects are additive

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Drug Combinations
Two bactericidil drugs:

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Drug Combinations
Two bactericidil drugs:
effects are synergistic

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Drug Combinations
Bacteriocidal and bacteriostatic:

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Drug Combinations
Bacteriocidal and bacteriostatic: antagonistic

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Factors that Impact Drug Effectiveness (4)

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Factors that Impact Drug Effectiveness (4)
1) Gneration time of the parasite
2) Intracellular vs. extracellular parasites
3) Bactericidal drugs do not work well in open body cavities
4) Treatment site in body tissues and fluids

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Factors that Impact Drug Effectiveness
Generation time of the parasite
longer time -->
reasons (2):

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Factors that Impact Drug Effectiveness
Generation time of the parasite
longer time --> more difficult treatment, start ASAP
reasons (2):
1) formation of cross-links in growing cells
2) number of errors in essential proteins

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Factors that Impact Drug Effectiveness
Intracellular vs extracellular parasites
Need what treatment for what parasites and why?

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Factors that Impact Drug Effectiveness
Intracellular vs extracellular parasites
Need what treatment for what parasites and why? need intense long-term treatment for facultative intracellular parasites - treatment buys time for development of CMI or humoral immunity

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Factors that Impact Drug Effectiveness
Treatment site in body tissues and fluids (4 examples/locations)

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Factors that Impact Drug Effectiveness
Treatment site in body tissues and fluids (4 examples/locations)
1) Abscess formation and necrosis - bactericidal drugs become ineffective
2) Foreign bodies & obstruction of excretory organs - limited circulation (less O2, nutrients, removal of waste products or obstruct urinary, respiratory or biliary tract --> decrease urine or lymphatic drainage)
3) Absorption by GI tract - easier to obtain effective levels in urine than serum
4) Penetration of CNS or blood brain barrier - usually limited