Antimicrobial drugs

• Chemotherapy: Use of drugs to treat disease.

• Antimicrobial Drugs: Interfere with growth of microbes within a host.

• Antibiotics: Substances produced by microbes that inhibit other microbes.

• Selective Toxicity: A drug’s ability to harm microbes without damaging the host.

• Broad-spectrum: Active against both Gram-positive and Gram-negative bacteria.

• Narrow-spectrum: Effective against specific types of microbes.

• Bactericidal: Kills bacteria.

• Bacteriostatic: Inhibits growth/reproduction of bacteria.

Five Major Modes of Action of Antimicrobial Drugs

1. Inhibition of Cell Wall Synthesis

• Targets: Peptidoglycan in bacterial cell walls (not present in humans).

• Drugs:

• Penicillin (natural & semi-synthetic): Blocks peptidoglycan cross-linking.

• Penicillin :

• Penicilinase- resistant penicillin

• Extended- spectrum peniciliins

• Penicillins = B- Lactamase inhibitors ( clavulanate, sulbactam, tazobactam)

• Augmentin: Amoxicillin + clavulanic acid (β-lactamase inhibitor).

• Cephalosporins: Inhibit cell wall synthesis; 2nd, 3rd. 4th, and 5th generations more effective against Gram - negatives.

• Polypeptide antibiotics :

• Bacitracin: Topical, against Gram (+).

-Vancomycin : Glycopeptide, imporant "first- line" against antibiotic resistant S. aureus

• Antimycobaterial antibiotics :

• Isoniazid (INH): Blocks mycolic acid synthesis in Mycobacterium tuberculosis.

• Ethambutol: Inhibits incorporation of mycolic acid into cell wall.

2. Inhibition of Protein Synthesis

• Targets: 70S bacterial ribosomes (not 80S eukaryotic, but can affect mitochondria).

• Drugs:

• Chloramphenicol: broad spectrum but toxic. Binds to 50S subunit, unhibits peptide bond formation.

• Aminoglycosides: (Streptomycin, Neomycin, Gentamicin)Broad spectrum, Changes shape of 30S subunit; cause mRNA misreading.

• Tetracyclines: Broad spectrum, interferes with tRNA attachment.

• Macrolides: Azithromycin (z-pack) - Broad spectrum, bind 50S; prevent translocation. Antiviral ( Ebola, Zika, influenza, RSV, COVID, rhinovirus) - stimulates interferons (antiviral immunity)

• Erythromycin: Gram- positives, binds 50S, prevents translocation.

3. Injury to Plasma Membrane

• Targets: Membrane structure, especially in fungi (ergosterol) and bacteria.

• Drugs:

• Polymyxin B: Topical, for Gram (-), Combines with bacitracin and neomycin in over-the counter preparation. ( Neosporin)

• Daptomycin: Effective against MRSA; disrupts membrane function.

• Antifungals (Amphotericin B, Miconazole): Bind to ergosterol, form pores in membrane.

4. Inhibition of Nucleic Acid Synthesis

• Targets: DNA/RNA synthesis enzymes.

• Drugs:

• Rifampin: Inhibits RNA synthesis; used for TB and leprosy. ( Antituberculosis)

• Quinolones/Fluoroquinolones (e.g., Ciprofloxacin): Inhibit DNA gyrase. Urinary tract infections

5. Inhibition of Synthesis of Essential Metabolites

• Targets: Enzyme pathways bacteria use for survival.

• Drugs:

• Sulfonamides (Sulfa drugs): Broad spectrum, Inhibit folic acid synthesis

Antiviral Drugs

• Not antibiotics

• Acyclovir: Guanine analog; inhibits viral DNA synthesis (used for HSV (herpes simplex) , VZV (Varicella- zoster (VZV) )

• Guanine analogue - inhibits DNA synthesis

• Provides symptomatic relief, lessens duration of outbreak

• Not a cure

• AZT (Zidovudine): Inhibits reverse transcriptase in HIV, DDI, DDC

• DNA nucleoslide analogues

• Used to treat HIV

• inhibit reverse transcriptase

• symptomatic relief, not a cure, apparently not life extending

• Protease Inhibitors (Indinavir): Prevent cleavage of viral proteins; used in HIV therapy.

• Uncoating Inhibitors (Amantadine): Prevent virus from releasing its genome (influenza).

• Neuraminidase Inhibitors (Zanamivir, Oseltamivir): Block release of viruses (influenza).

• Interferons: Boost host immunity; used for hepatitis

• Viral protease required for cleavage of viral polypeptide precursors

• Promising results

• Protease inhibitors in combination with other drugs ( i.e AZT) has reduced amount of virus below current limits of detection.

Antifungal Drugs :

• Polyenes (Amphotericin B): Bind ergosterol → disrupt membrane.

• Azoles (Miconazole, Ketoconazole): Inhibit ergosterol synthesis.

Antibiotic Resistance

• A variety of mutations can lead to antibiotic resistance

• Mechanism of antibiotic resistant :

1. Enzymatic destruction of drug

2. Prevention of penetration of drug

3. Alteration of drug's target site (altered ribosome)

4. Rapid ejection of the drug ( Efflux pumps)

Causes of Resistance:

• Misuse (not finishing antibiotics, using for viral infections).

• Use in animal feed.

• Use of outdated/leftover drugs.

• Disk-diffusion (Kirby-Bauer) test: Assesses antibiotic effectiveness via zone of inhibition.

Future of chemotherapeutic Agents :

• Antimicrobial peptides

• Broad spectrum antibiotics from plants and animals

  • Squalamine (sharks)

  • Protegrin (pigs) - antiviral

  • Magainin ( frogs)

  • So far has failed clinical trials or not been approved for use

• Antisense agents :

• Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription.

• Teixobactin: Discovered 2015.

• Isolated from soil bacterium

• Narrow spectrum - Gram (+) bacteria but includes Mycobacterium tuberculosis

• Effective against MRSA, Clostridium difficile and anthrax

• Targets lipid precursors in cell wall synthesis. No resistance observed in lab.

• Halicin: Found via AI, failed diabetes drug ;

• MIT used an algorithm to scan exisiting drugs and determine potential antibiotic activity

• was discovered as a new antibiotic

• Mechanism of action : Halicin causes bacteria to store excess iron inside cell. This disrupts protonmotive force ( electrochemical gradient) inhibiting ATP production.