Antibacterial Resistance Mechanisms and Drug Classes

Posted on Dec 15, 2024 in Biology

Antibacterial Resistance: Mechanisms of Action and Spectrum

**Beta-Lactams**

  • **Mechanism of Action:** Inhibit cell wall synthesis by inhibiting peptidoglycan polymerization.
  • **Resistance Mechanisms:**
    • Beta-lactamase enzyme synthesis.
    • Altered target site.
  • **Spectrum:**
    • Broad (Benzylpenicillin).
    • Reduced (Ampicillin).
  • **Antibacterial Activity:** Bactericidal.
  • **Features:** No antibiotic is toxic and old (1940s), routine clinical use.
  • **Representatives:** Ampicillin, Penicillin.

**Glycopeptides**

  • **Mechanism of Action:** Inhibit transglycosylation, affecting the synthesis of plasmid-type peptidoglycan.
  • **Spectrum:** Reduced.
  • **Antibacterial Activity:** Bactericidal.
  • **Features:** Toxic, management should be controlled.
  • **Representatives:** Vancomycin, Teicoplanin.

Aminoglycosides

  • **Mechanism of Action:** Inhibit protein synthesis by binding to the 30S ribosomal subunit, altering the translation of the synthesized protein.
  • **Resistance Mechanisms:** Aminoglycoside-inactivating enzymes, mutations in some antibiotics.
  • **Spectrum:** Broad.
  • **Antibacterial Activity:** Bactericidal.
  • **Features:** High percentage hydrophilic, none, good distribution, gastric absorption but not in lipid places, extensive clinical use in Gram-negative bacteria.
  • **Representatives:** Streptomycin (natural), Amikacin (semisynthetic).

**Tetracyclines**

  • **Mechanism of Action:** Inhibit protein synthesis (reversible binding to 30S rRNA).
  • **Resistance Mechanisms:** Ribosomal mutation.
  • **Spectrum:** Broad.
  • **Antibacterial Activity:** Bacteriostatic.
  • **Features:** Protection, acts on anaerobic bacteria and spirochetes.
  • **Representatives:** Doxycycline, Tetracycline.

**Oxazolidinones**

  • **Mechanism of Action:** Inhibit protein synthesis.
  • **Features:** New antibiotic, little toxicity.
  • **Spectrum:** Reduced.
  • **Representatives:** Linezolid (acts on Gram-positive bacteria), Eperezolid.

Macrolides

  • **Mechanism of Action:** Inhibit protein synthesis by binding to 23S rRNA of the 50S ribosomal subunit, blocking the translocation of protein synthesis.
  • **Spectrum:** Reduced.
  • **Resistance Mechanisms:** Ribosomal mutation, enzyme inactivation.
  • **Antibacterial Activity:** Bacteriostatic.
  • **Features:** Used in pediatrics, oral administration, natural and semisynthetic source.
  • **Representatives:** Erythromycin, Clarithromycin.

**Chloramphenicol**

  • **Mechanism of Action:** Oral administration: Inhibition of protein synthesis by inhibiting peptidyl transferase, preventing the synthesis of peptide bridges.
  • **Features:** Oral administration: Synthesis of the enzyme acetyltransferase, old antibiotic (1944), intravenous administration has toxic effects (R: anemia, I: bone marrow suppression).
  • **Spectrum:** Broad.
  • **Antibacterial Activity:** Bacteriostatic.

**Streptogramins**

  • **Mechanism of Action:** Oral administration: Inhibition of protein synthesis.
  • **Spectrum:** Limited range (Gram-positive bacteria).
  • **Features:** Semisynthetic source, synergy occurs in the combination of quinupristin and dalfopristin.

**Lincosamides**

  • **Mechanism of Action:** Bind to the 50S ribosomal subunit, inhibiting protein synthesis.
  • **Resistance Mechanisms:** MLS resistance.
  • **Spectrum:** Reduced (Gram-positive bacteria).
  • **Antibacterial Activity:** Bacteriostatic.
  • **Features:** Act on strict anaerobes, check the bone, good oral administration.
  • **Representatives:** Lincomycin (natural), Clindamycin (semisynthetic).

**Quinolones**

  • **Mechanism of Action:** Act on DNA replication by inhibiting DNA gyrase, responsible for DNA supercoiling.
  • **Resistance Mechanisms:** Plasmid resistance (II).
  • **Spectrum:** Broad.
  • **Antibacterial Activity:** Bactericidal.
  • **Features:** Lower toxicity, good concentration in urine, absence.
  • **Representatives:** Ciprofloxacin (II), Levofloxacin (III).

**Metronidazole**

  • **Mechanism of Action:** Alters bacterial DNA, uptake or elimination of cytotoxic metabolites produced.
  • **Spectrum:** Reduced, acts against strict and facultative anaerobes.

**Rifamycins**

  • **Mechanism of Action:** Inhibit the RNA polymerase subunit, preventing the start of transcription.
  • **Resistance Mechanisms:** High frequency of mutation.
  • **Spectrum:** Broad.
  • **Antibacterial Activity:** Bactericidal.
  • **Features:** Lipid-soluble, natural source.
  • **Representatives:** Rifampicin.

**Cotrimoxazole**

  • **Mechanism of Action:** Interferes with intermediary metabolism by inhibiting folic acid synthesis.
  • **Resistance Mechanisms:** Plasmid-type (encoding the enzyme dihydrofolate reductase with trimethoprim affinity), chromosomal (mutation).
  • **Spectrum:** Broad.
  • **Antibacterial Activity:** Bactericidal.
  • **Representatives:** Sulfamethoxazole + Trimethoprim.

Antiviral Agents

  1. **Viral DNA Polymerase Inhibitors:** Inhibit viral replication. Active against herpes virus (e.g., Foscarnet, Acyclovir, Ganciclovir, Ribavirin).
  2. **Reverse Transcriptase Inhibitors:** Used for HIV (e.g., AZT – Azidothymidine).
  3. **Ion Channel Blockers:** Amantadine, used for influenza A.
  4. **Protease Inhibitors:** Used for HIV (e.g., Indinavir, Ritonavir, Saquinavir).
  5. **Oseltamivir:** Inhibits viral replication in influenza.

Antiprotozoal Agents

  • **Mechanism of Action:** Nucleic acid synthesis inhibitors eliminate parasites.

Antifungal Agents

  • **Representatives:** Amphotericin B, Nystatin, Azoles (Imidazoles and Triazoles), Flucytosine, Nucleoside analogs, Polyene antibiotics.
  • **Mechanism of Action:** Interfere with the fungal membrane or its synthesis.
  • **Indications:** Candidiasis, skin or intestinal infections, uterine infections, corneal tract infections.

Antibiotic Action at the Cellular Level

  • **On Folic Acid:** Blocks the synthesis and action of folic acid.
  • **On the Cell Wall:** Blocks the synthesis of peptidoglycan through the inhibition of transport enzymes in cell wall synthesis.
  • **On the Membrane:** Forms pores in the membrane, breaking the integrity of the cell.
  • **At the Core Level:** Interferes with the functions of the bacterial chromosome by inhibiting transcription.

Mechanisms of Antibiotic Resistance

  • Modification of the antibiotic target.
  • Modification of the antibiotic (inactivation).
  • Modification of the input via porins.
  • Antibiotic pumping system into the cell.

Sterilization

  • **Definition:** Complete destruction of microorganisms, including resistant forms such as spores, non-enveloped viruses, and fungi.
  • **Physical Methods:** Dry heat, wet heat, filtration, ionizing radiation (X-rays, gamma rays, UV rays).
  • **Chemical Methods:** Ethylene oxide (ETO), hydrogen peroxide (H2O2) in plasma.
  • **Gaseous Methods:** Peracetic acid (oxidizing agent, non-toxic, excellent activity – acetic acid + O2), glutaraldehyde.

*Escherichia coli*