Antibiotics and Host Defense Mechanisms

Antibiotics: Principles of Antimicrobial Therapy

  • Goal: Destroy infective agent without harming the host.

  • Selective Toxicity (Stox): Kill or inhibit pathogens selectively.

    • Best drugs target structures unique to pathogens (e.g., Penicillins).

    • More toxic drugs affect structures common to both pathogens and host cells.

  • Origins: Natural, semisynthetic (chemically altered natural ABs), or synthetic (laboratory-created).

  • Spectrum:

    • Broad: Effective against multiple groups; can disrupt normal flora (e.g., tetracyclines).

    • Narrow: Targets specific groups (e.g., polymyxin).

  • Bacteriostatic: Prevents cell growth.

  • Bactericidal: Kills cells.

  • Administration: Oral (affected by pH and enzymes) or injection (muscle, skin, intravenous).

Discovery of Antibiotics

  • Alexander Fleming (1928): Noticed Penicillium notatum mold inhibited Staphylococcus aureus growth

Mechanisms of Drug Action

  • Targets:

    • Cell wall synthesis

    • Folic acid synthesis

    • Nucleic acid (DNA & RNA) structure/function

    • Cell membrane structure/function

    • Protein synthesis

I. Drugs Targeting Cell Wall

1. Penicillins:

  • Blocks peptidoglycan cross-linking.

  • Natural, semi-synthetic; contains thiazolidine, B-lactam rings, and variable side chain.

  • Natural penicillin's: Effective against G+ cocci & G- bacteria; susceptible to penicillinases.

  • Penicillinases (B-Lactamases): Cleave B-lactam ring; clavulanic acid inhibits them.

  • Semisynthetic penicillins: Modified side chains; broader spectrum but may not resist penicillinase.

    • Examples: ampicillin, carbenicillin, amoxicillin

    • Newer ones (resist penicillinase): Methicillin, nafcillin

2. Cephalosporins:

  • B-lactam ring altered chemically; similar action to penicillin's; fewer allergies.

3. Carbapenems:

  • B-lactam rings; used for penicillin allergies; AB of last resort due to side effects; treats MDR bacteria.

4. Glycopeptides:

  • No B-lactam ring; amino acid/peptide chain; IV administration.

    • Vancomycin: Ab of last resort.

II. Drugs Targeting Folic Acid Synthesis

  • Sulfonamides (Sulfa Drugs):

    • First modern AB drugs; synthetic; common allergies.

    • Mechanism: Inhibit DHPS enzyme that cleaves PABA to make tetrahydrofolic acid (bacterial macronutrient).

    • Competitive inhibition: Sulfa drug binds to DHPS, preventing PABA binding.

III. Drugs Targeting DNA or RNA

  • Quinolones:

    • High potency, broad spectrum; target DNA replication.

    • Example: Ciprofloxacin, xifaxan.

  • Rifampin (Rifampicin):

    • Targets RNA polymerase; inhibits transcription.

    • Used in drug cocktails for TB and leprosy.

IV. Drugs Targeting Cell Membranes

  • Bind to LPS, disrupt membranes; AB of last resort.

1. Polypeptide drugs:

  • Polymyxin: Toxic to kidneys.

2. Lipopeptide:

  • Daptomycin

V. AB Drugs Targeting Protein Synthesis

  • Blocks translation by binding to ribosome-mRNA complex.

  • Prokaryotic & eukaryotic ribosomes differ, allowing Stox.

1. Aminoglycosides:

  • Distort ribosome; cause translation errors; broad spectrum.

2. Tetracyclines:

  • Block protein assembly; broad spectrum; GI disruption, hard tissue deposition side effects.

3. Glycylcyclines:

  • Blocks protein assembly; Newer semisynthetic derivates of tetracyclines

4. Chloramphenicol:

  • Blocks protein assembly; AB last resort due to risk of aplastic anemia.

5. Erythromycins:

  • Blocks protein assembly; broad spectrum; decreased toxicity.

Antifungals

  • Fungal cells = eukaryotic, posing Stox challenges.

1. Cell Wall:

  • Echinocandin drugs target B-glucan in fungal cell walls.

2. Plasma Membrane:

  • Target ergosterol (analogous to cholesterol in animal cells).

- Polyenes: Bind ergosterols, causing ion leakage (e.g., Amphotericin B).
- Azoles: Inhibit ergosterol synthesis; treat systemic & topical mycoses.

3. Inhibition of Microtubules:

  • Griseofulvin: Oral, systemic & topical mycoses.

Anti-protozoans

  • Target intracellular compounds; Stox is a problem.

- Anti-malarial: Quinine & Artemisinin.

  • Other antiprotozoals: Nitrazoxanide (blocks respiration), Metronidazole (prevents DNA replication).

Anti-helminthics

  • Stox is a problem.

    • Mebendazole & albendazole: Blocks transport of materials into cells, treats nematode infections.

    • Praziquantel: Targets membranes, treats trematodes & tapeworms.

    • Ivermectin: Interferes with parasite nervous system, treats nematodes.

Anti-viral

  • Stox is also hard

  • Major modes of action:

    1. Block penetration

    2. Block transcription & translation of viral molecules

    3. Prevent maturation

  • Antivirals: Oseltamivir (influenza), Acyclovir (herpes), Ribavirin (respiratory infections, hepatitis C).

  • Interferon (IFN): Treats hepatitis C & genital warts (HIV+); has serious side effects.

Drug Resistance

  • Microbes adapt to tolerate increasing AB amounts.

  • Types: Intrinsic (spontaneous mutation) & Acquired (gene acquisition via HGT).

  • Human overuse: Over-prescription, household products, improper use, globalization, vet over prescription

  • The hospital factor: continual exposure to AB, house susceptible patients

Host Defense Mechanisms: Nonspecific and Specific

- 1st line of defense (Non-specific):

  • Barriers blocking invasion: skin, mucous membranes, secretions.

- 2nd line (Non-specific):

  • Internalized system of protective cells: inflammation & phagocytosis.

- 3rd line (Specific):

  • Acquired immunity involving lymphocytes (WBC)

1st Line of Defense: Physical Barriers

  • Skin: Epithelial cells with keratin; waterproof.

  • Mucous Membranes: Epithelial tissue secretes mucus; lacks keratin.

    • Respiratory tract: Nasal hair, mucus, ciliated epithelium.

    • Genitourinary tract: Urine flow, vaginal secretions.

1st Line of Defense: Chemical Barriers

  • Skin & mucus membranes: Sebaceous secretion, lysozyme (%pH)(\%pH), lactic acid.

  • Stomach: Hydrochloric acid.

  • Intestines: Digestive juices, bile.

  • Other: Semen, vaginal pH.

The 2nd & 3rd Lines of Defense: Immunology

  • Surveillance, recognition (self vs. non-self), destruction of foreign entities.

  • Markers: Molecules on cell surfaces for identification.

  • PAMPs: Pathogen-associated molecular patterns on microbial surfaces.

    • Ex: Peptidoglycan, LPS, dsRNA

  • PRR: Patterns recognition receptors on phagocytes, dendritic cells, & endothelial cells.

Systems Involved in Immune Defenses

1. Lymphatic system 2. blood streams

Stem cells: undifferentiated precursor to blood cells

  • WBC (Leukocytes): Granulocytes, Agranulocytes

  • Granulocytes: Phagocytosis & inflammation.

  • Agranulocytes: Lymphocytes, Monocytes, immune memory, antibodies

    • Monocytes: Largest of all WBC - Become macrophages, dendritic cells

2nd Line of Defense: Phagocytosis

  • Functions: Surveillance, recognition, destruction.

  • Mechanism: PRR recognize PAMPs.

  • Phagocytes: Neutrophils, monocytes, macrophages, dendritic cells.

  • Chemotaxis: WBC migration to injury/infection site.

  • Phagolysosome formation & killing: Lysosomes fuse with phagosome to digest material.

2nd Line of Defense: Inflammation

  • Classic signs & symptoms: Rubor, tumor, dolor, color, loss of function.

  • Events: Chemokines & vasodilation, Exudate/Edema, Pus.

  • Neutrophils coverage, Repair from Monocytes & macrophages,

  • Diapedesis: WBC movement from bloodstream to tissues.

3 Fevers

  • Elevated body temp - assists inflammation

  • Pyrogens: Substances that, when released, produce fever.
    Exogenous: from outside body & Endogenous: from inside body

  • Benefits of fever: Inhibits microbes, increases metabolism & immune reactions.

4 antimicrobial proteins

A. interferon (IFN): Involved in defense against microbes & used in therapy against viral infections & cancer
B. complement: Puncture holes in bac. Cell
C. Fe+ - binding proteins: Rate-limiting factor in bac growth & cannot be used by bac
D. antimicrobial peptides - insert themselves into bac. Membranes & kill by lysis