Chapter 14

Who developed the first antimicrobial drug through scientific screening?

Paul Ehrlich, who discovered Salvarsan to treat syphilis

What was the first synthetic antimicrobial, and who developed it?

Prontosil, developed by Klarer, Mietzch, and Domagk

Who discovered the first natural antibiotic?

Alexander Fleming discovered penicillin from Penicillium notatum

Who determined penicillin’s structure and enabled semisynthetic versions?

Dorothy Hodgkin used X-ray crystallography

Who discovered several soil-based antimicrobials like streptomycin?

Selman Waksman; discovered many from Actinomycetes

What’s the difference between narrow and broad-spectrum drugs?

Narrow: Targets specific microbes (preferred)

Broad: Targets wide range but can cause superinfections

Why is narrow spectrum usually better?

Less disruption to normal flora and lower chance of resistance development

How does the route of administration affect drug concentration?

IV is fastest and most direct; oral is slower and may degrade in digestion

Give an example of a synergistic interaction

Trimethoprim + Sulfamethoxazole (Bactrim) - boosts efficacy

Give an example of an antagonistic interaction

Rifampin + birth control - reduces contraceptive effectiveness

Cell Wall Synthesis: What are B-lactam drugs?

Penicillins, cephalosporins, carbapenems, monobactams (inhibit peptidoglycan cross-linking

Cell Wall Synthesis: What’s vancomycin’s MOA?

Binds to peptide chain ends, blocking cell wall extension (G+ only)

Cell Wall Synthesis: How does bacitracin work?

Blocks transport of peptidoglycan precursors across membrane (derived from B. subtilis)

Protein Synthesis: What drugs target the 30s subunit?

Aminoglycosides (e.g. streptomycin, gentamicin, neomycin), tetracyclines - block tRNA or proofreading

Protein Synthesis: What drugs target the 50s subunit?

Macrolides (broad), lincosamides (narrow), chloramphenicol, oxazolidinones (e.g. linezolid)

Membrane Function Disruptors: How do polymyxins work?

Disrupt Gram-negative membranes (lipophilic, not selective)

Membrane Function Disruptors: What’s the MOA of daptomycin?

Inserts into and disrupts Gram-positive membrane.

Nucleic Acid Synthesis: What does metronidazole target?

DNA synthesis (anaerobes and protozoa); broad-spectrum, DNA replication

Nucleic Acid Synthesis: What’s rifampin’s MOA?

Blocks RNA polymerase (used for M. tuberculosis); hepatotoxic

Nucleic Acid Synthesis: What do fluoroquinolones inhibit?

DNA gyrase (broad-spectrum)

Metabolic Pathway: What do sulfa drugs do?

Inhibit folic acid synthesis & production of pyrimidines & purines; often combined with trimethoprim

Metabolic Pathway: What is isoniazid used for?

Blocks mycolic acid synthesis in mycobacteria

Metabolic Pathway: What’s the MOA of diarylquinolines?

Inhibit ATP synthase in Mycobacterium

Triple Antibiotic Ointment (e.g. Neosporin): What are the 3 drugs and their MOAs?

Bacitracin: Inhibits cell wall synthesis

Neomycin: Inhibits protein synthesis (30s)

Polymyxin B: Disrupts Gram-negative membrane

Antifungal: Common MOA of antifungals?

Disruption of ergosterol in fungal membranes.

Antifungal: Name an antifungal that binds ergosterol

Polyenes (e.g., amphotericin B)

Antifungal: What do echinocandins inhibit?

B(1-3) glucan synthesis – "penicillin for fungi."

Antiprotozoal: What does metronidazole treat in protozoa?

Giardia, dysentery – inhibits DNA synthesis

Antiprotozoal: What is atovaquone’s target?

Malaria, babesiosis, toxoplasmosis; inhibits electron transport

Anthelminthic: MOA of mebendazole?

Inhibits microtubule formation

Anthelminthic: What does Ivermectin target?

Blocks neuronal transmission – causes paralysis in worms

Anthelminthic: MOA of praziquantel?

Induces calcium influx - paralysis

Antiviral: What is an ART cocktail?

Combination of HIV drugs to block multiple steps of viral replication

Antiviral: What are the 4 types of HIV inhibitors?

1. Reverse transcriptase: Block RNA - DNA

2. Protease: Block process of viral proteins

3. Integrase: Prevent integration of viral DNA

4. Fusion inhibitors: Prevent binding virus to host cell

How does resistance arise?

Natural selection from misuse, low dosing, noncompliance

Name 5 mechanisms of antimicrobial resistance

1. Enzymatic drug inactivation (e.g. B-lactamase)

2. Target modification

3. Efflux pumps

4. Overproduction of target

5. Mimicry/bypass of target

What are superbugs?

Multidrug-resistant organisms, hard to treat

What are ESKAPE pathogens?

Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter - highly resistant

What is MIC?

Minimum Inhibitory Concentration – lowest amount to inhibit growth

What is MBC?

Minimum Bactericidal Concentration – lowest amount to kill bacteria

What does the Kirby-Bauer test measure?

Zone of inhibition around drug disks (qualitative)

Is new antimicrobial discovery increasing?

No, it’s declining

What are some new approaches to drug discovery?

• Semisynthetic derivatives

• High-throughput screening

• iChip and teixobactin

• Marine microbes

• Inhibiting resistance or virulence instead of killing