Overview
This lecture covers cell wall synthesis inhibitors, focusing on the classification, structure-activity relationships, mechanisms of action, resistance, clinical uses, and adverse effects of beta-lactam antibiotics and glycopeptides.
Classification of Cell Wall Synthesis Inhibitors
- Cell wall synthesis inhibitors include beta-lactam drugs and non-beta-lactam drugs.
- Four classes of beta-lactam drugs: penicillins, cephalosporins, carbapenems, and monobactams.
- Non-beta-lactam cell wall inhibitor: vancomycin (a glycopeptide).
- Penicillins are further divided into natural, penicillinase-resistant, aminopenicillins, and anti-pseudomonal penicillins.
Structure-Activity Relationship & Mechanism of Action
- All beta-lactam antibiotics contain a beta-lactam ring essential for antibacterial activity.
- Antibiotic properties, spectrum, and resistance are determined by the side chain attached to the core structure.
- Beta-lactam antibiotics inhibit the last step of peptidoglycan synthesis by binding to penicillin-binding proteins (PBPs), also called transpeptidases.
- Inhibition weakens the cell wall, causing bacterial lysis (bactericidal effect).
- Selective toxicity: human cells lack peptidoglycan cell walls.
Mechanisms of Resistance
- Resistance mechanisms include: beta-lactamase (enzyme) production, alteration of PBPs, and impaired drug penetration.
- MRSA (methicillin-resistant Staphylococcus aureus) modifies the PBP, resulting in resistance to most beta-lactams.
- Beta-lactamase inhibitors (e.g., clavulanic acid) protect beta-lactam antibiotics from degradation.
Cephalosporins & Carbapenems
- Cephalosporins divided into five generations, with increased gram-negative coverage in later generations.
- Fourth and fifth generations are active against both gram-positive and gram-negative bacteria; fifth is effective against MRSA.
- Carbapenems (e.g., imipenem) have broad-spectrum activity and are used for severe or hospital-acquired infections; always co-administered with cilastatin.
Monobactams & Glycopeptides
- Monobactam (aztreonam) is active mainly against aerobic gram-negative organisms.
- Glycopeptide (vancomycin) inhibits an earlier stage of cell wall synthesis and is effective against MRSA and Clostridioides difficile colitis.
Adverse Effects
- Common adverse effect: hypersensitivity (can range from rash to anaphylaxis).
- Cross-allergy exists between penicillins.
- Vancomycin can cause nephrotoxicity, ototoxicity, and Red Man syndrome.
Key Terms & Definitions
- Beta-lactam ring — four-membered lactam structure key to antibacterial activity of beta-lactam drugs.
- Penicillin-binding protein (PBP) — bacterial enzyme (transpeptidase) targeted by beta-lactam antibiotics.
- Beta-lactamase — bacterial enzyme that hydrolyzes beta-lactam ring, leading to antibiotic resistance.
- Glycopeptide — class of antibiotics, e.g., vancomycin, that inhibit cell wall synthesis at an earlier stage than beta-lactams.
- Red Man syndrome — adverse reaction to vancomycin, presenting as flushing due to rapid infusion.
Action Items / Next Steps
- Review structural differences among beta-lactam antibiotics.
- Memorize the classification and spectrum of penicillins and cephalosporins.
- Understand mechanisms of resistance and the role of beta-lactamase inhibitors.