Antibacterial Agents & Resistance

Question 1

Discuss the origin of antimicrobials

Answer 1

• Salvarsan documented 1st antimicrobial = antisyphilitic
• Sulfonamide is first sulfa drug - competitive inhibitor to para-aminobenzoic acid (folate metabolism)
• Alexander Fleming notified no staph colonies around penicillin in culture - Chain and Florey isolated compound
• Prontosil Drug
• Waksman isolated streptomycin from soil bacteria (Streptomyces griseus)

Question 2

Explain the concept of selective toxicity and its relationship to antimicrobial agents

Answer 2

• antibiotics cause greater harm to microorganisms than human host
• expressed as a therapeutic index
  
  • lowest dose toxic to patient divided by dose typically used for treatment –> lower therapeutic index = less toxic to patient

Question 3

Discuss the desired antimicrobial properties and pharmacologic activities of antimicrobial agents

Answer 3

• inhibit growth or kill bacterium
• narrow or broad spectrum
  - con of broad-spectrum = kill off normal flora
• Negatives
  - antimicrobial resistance
  - suppresion of normal flora
  - allergic reactions
  - toxic effects

Question 4

Explain the roles of bacterial chromosomal mutations, plasmids, transposons and integrons in the generation of antibiotic resistance mechanisms

Answer 4

Mutations: spontaneous, not very effective with drugs that have multiple targets
Plasmids: provides stability, transmissibility; carry multiple resistance cassettes
Transposons:
Integrons:

Question 5

Describe the major mechanisms of bacterial resistance to antibiotics

Answer 5

• Mycoplasma has no cell wall
• Mycobacterium has impermeable waxy coat
• chlamydia, rickettsia, brucella, legionella - live in host cells

Question 6

What is a bacteriostatic drug? And why use them?

Answer 6

• inhibits growth

- relies on host immunity to eliminate pathogen

Question 7

What is a bactericidal drug?

Answer 7

kills the bacteria

Question 8

Semisynthetic drugs

Answer 8

• alteration of drug structure to give new properties
• Penicillin G altered to make ampicillin
• broadened spectrum of antimicrobial effect

Question 9

What is a synergistic drug interaction?

Answer 9

one drug enhances another

Question 10

What is an antagonsistic drug interaction?

Answer 10

one drug interferes with another

Question 11

What is a vertical evolution?

Answer 11

spontaneous gene mutation (antibiotic resistance)

-low rate

Question 12

How is mycoplasma resistant to antibiotics?

Answer 12

no cell wall

Question 13

How is mycobacterium resistant to antibiotics?

Answer 13

impermeable wax coating

Question 14

What bacteria live in host cells and therefore are resistant to antibiotics?

Answer 14

Chlamydia, Rickettsia, Brucella, Legionella

Question 15

Mechanisms to resist antibiotics?

Answer 15

• drug inactivation
• alteration of drug molecule (Penicillin Binding Protein)
• decreased uptake of the drug
• increased elimination of the drug

Question 16

Describe beta-lactams regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms

Answer 16

• all bind PBP (responsible for cross-linking petides in proteoglycan synthesis)
• all types have B-lactam rings (square, 3Cs, 1 N)
• low oral bioavailability, cannot pass thru BBB due to polarity
• ineffective against intracellular organisms
• excreted in urine
• carbapenam has broadest spectrum
• chephalosporins is more potent against gram (-)s than penicillin

Question 17

Describe beta-lactamase inhibitors regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms

Answer 17

-named after the substrate

-

Question 18

Describe glycopeptides regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms

Answer 18

• large peptides w/ few monosaccharides
• gram-(+) only; can’t penetrate cell wall of gram (-)
• binds peptide ends
• main indication is B-lactam resistant Gram (+) bacteria (MRSA)
• poorly absorbed in GI tract
• lactobacilli resist because of unique peptide ends: D-alanyl-D-lactate – VanA, VanB, VanD enables
• plasmid associated resistance

Question 19

What type of drug target has a high therapeutic index?

Answer 19

cell wall synthesis –> we don’t have cell walls

Question 20

Describe cephalosporins

Answer 20

• beta-lactase
• chemical structure makes them resistant to beta-lactamases
• low affinity for gram-(+) bacteria

Question 21

Describe carbapenems

Answer 21

• very resistant to B-lactamases
• effective against a wide range of gram (+) and (-)organisms
• can be given to patients with penicillin allergy

Question 22

Describe monobactams

Answer 22

• very resistant to beta-lactamases
• primarily effective against enterobaccteriaceae
• can be given to patients with penicillin allergy

Question 23

Describe monobactams

Answer 23

• very resistant to beta-lactamases
• primarily effective against enterobaccteriaceae
• can be given to patients with penicillin allergy

Question 24

Explain the advantages and clinical use of semisynthetic penicillins (oxacillin, cloxacillin, ampicillin, and amoxicillin)

Answer 24

• you can change the side group to make the drug more bioavailable and have a broader spectrum
• 3 goals: acid stability, B-lactamase resistance, extended spectrum

Question 25

Discuss the mechanism of action, clinical use, and spectrum of activity of polypeptide antibiotics

Answer 25

Bacitracin -inhibit dephosphorylation & recycling of bactoprenol -damage cytoplasmic membrane & inhibit transcription -low therapeutic index -- only use topicaly Polymyxins -cyclic polypeptides -insert into membranes to increase cell permeability -most effective against gram (-)s -nephrotoxicity -- topical application only

Question 26

Compare and contrast antibacterial agents that interfere with protein synthesis regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms

Answer 26

Aminoglycosides -irreversibly bind 30S subunit --> distortion & malfunction, blocks transcription -not effective against anaerobes, enterococci, and streptococci -in combo with B-lactam drugs -- more permeability -low oral bioavailability -use for severe life-threatening gram (-) infections -side effects: nephrotoxicity & ototoxicity -resistance through modifying proteins and alteration of ribosomal target Tetracyclines -reversibly bind 30S subunit --> block attachment of tRNA, prevents protein elongation -effective against gram-(+) and (-) -resistance due to decreased penetration into cell, active efflux out of cell (transposon mediated), alteration of ribosomal target, enzymatic modification of drug Macrolides -reversibly bind to 50S subunit --> prevents continuation of protein synthesis -good GI absorption, wide distribution -effective against gram (+), some gram (-) coccobacilli and intracellular bacteria -for patients allergic to penicillin -resistance due to methylation of 50S subunit, enzymatic modification of drug, efflux of antibiotic

Question 27

Discuss cross-resistance between macrolides, lincosamides, and streptogramins

Answer 27

-due to methylated 50S ribosome

Question 28

Discuss antibacterial agents that interfere with nucleic acid synthesis regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms

Answer 28

Quinolones - inhibit action of topoisomerase DNA gyrase - effective against gram (+) and gram (-) - resistance due to alteration of DNA gyrase, altered uptake, and efflux (all due to a mutation)

Question 29

Explain the mechanisms of synergism between sulfonamides and trimethoprim

Answer 29

-metabolic pathway inhibitors -inhibit prooduction of folic acid Sulfonamides -sulfa drug family -inhibit growth of gram-(+) and (-)s -- competitive inhibition -structurally similar to para-aminobenzoic acid in folate pathway (humans don't have this enzyme) -resistance due to plasmid Trimethoprim -inihibits dihydrofolate reductase -resistance due to plasma encoded alternative enzyme

Question 30

Discuss antibacterial agents for treating M. tuberculosis infection regarding regarding chemical structure, mechanism of action, spectrum of activity, clinical use, and resistance mechanisms

Answer 30

Rifampin Streptomycin Isoniazid --> inihibits synthesis of mycolic acid Ethambutol --> inihibits arabinogalactan synthesis in cell wall Pyrazinamide --> disrupts proton motive force; inhibits FAS1 -resistance due to chromosomal gene mutations -these first line drugs have low toxicity