Antibacterial Drugs: Mechanisms and Selectivity

• Antibacterial drugs target essential bacterial processes, aiming to kill (bactericidal) or inhibit bacterial growth (bacteriostatic).
• Selective toxicity is vital, drugs should harm bacteria without significantly affecting the host.

Mechanisms of Action

• Inhibition of cell wall synthesis is a common antibacterial mechanism.
• Penicillins, cephalosporins, carbapenems, and monobactams inhibit peptidoglycan synthesis which is a vital part of the bacterial cell wall.
• Glycopeptides (e.g., vancomycin) also inhibit cell wall synthesis but bind to a separate target.
• Inhibition of protein synthesis occurs by targeting bacterial ribosomes (30S or 50S subunits).
• Aminoglycosides, tetracyclines, and glycylcyclines bind to the 30S ribosomal subunit.
• Macrolides, lincosamides, chloramphenicol, and streptogramins bind to the 50S ribosomal subunit.
• Inhibition of nucleic acid synthesis is another antibacterial target.
• Fluoroquinolones inhibit DNA gyrase and topoisomerase IV, which are essential for DNA replication and repair.
• Rifampin inhibits bacterial RNA polymerase.
• Inhibition of metabolic pathways occurs by targeting enzymes involved in folate synthesis.
• Sulfonamides and trimethoprim inhibit different steps in the folate synthesis pathway.
• Disruption of cell membrane integrity occurs with polymyxins, by interacting with bacterial cell membranes, which leads to increased permeability and cell death.

Antibacterial Spectrum

• Antibacterial drugs are classified based on spectrum of activity, that is, the range of bacteria they can effectively target.
• Broad-spectrum antibiotics are effective against a wide range of bacteria, including both Gram-positive and Gram-negative bacteria.
• Narrow-spectrum antibiotics are effective against a limited range of bacteria.

Resistance Mechanisms

• Antibacterial resistance is a major global health threat.
• Mechanisms of resistance include:
  • Enzymatic inactivation of the drug (e.g., beta-lactamases hydrolyzing penicillins).
  • Modification of the drug target (e.g., mutations in penicillin-binding proteins reducing affinity for beta-lactams).
  • Decreased drug accumulation (e.g., reduced uptake or increased efflux).
  • A bypass of the inhibited metabolic pathway can cause antimicrobial resistance.
• Horizontal gene transfer like conjugation, transduction, and transformation facilitates the spread of resistance genes between bacteria..

Beta-Lactam Antibiotics

• Penicillins contain a beta-lactam ring and inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs).
• Natural penicillins (e.g., penicillin G) are primarily active against Gram-positive bacteria.
• Penicillinase-resistant penicillins (e.g., oxacillin) are resistant to breakdown by bacterial beta-lactamases.
• Aminopenicillins (e.g., ampicillin, amoxicillin) have improved activity against Gram-negative bacteria.
• Extended-spectrum penicillins (e.g., piperacillin) have a broader spectrum of activity, including activity against Pseudomonas aeruginosa.
• Beta-lactamase inhibitors (e.g., clavulanate, sulbactam, tazobactam) are often combined with penicillins to protect them from inactivation by beta-lactamases.
• Cephalosporins are another class of beta-lactam antibiotics, also inhibiting cell wall synthesis.
• Cephalosporins are classified into generations based on their spectrum of activity.
  • First-generation cephalosporins (e.g., cefazolin) have good activity against Gram-positive bacteria.
  • Second-generation cephalosporins (e.g., cefuroxime) have improved activity against Gram-negative bacteria.
  • Third-generation cephalosporins (e.g., ceftriaxone, ceftazidime) have broad-spectrum activity, some with activity against Pseudomonas aeruginosa.
  • Fourth-generation cephalosporins (e.g., cefepime) have broad-spectrum activity and are more resistant to beta-lactamases.
  • Fifth-generation cephalosporins (e.g., ceftaroline) have activity against methicillin-resistant Staphylococcus aureus (MRSA).
• Carbapenems (e.g., imipenem, meropenem, ertapenem, doripenem) are broad-spectrum beta-lactam antibiotics.
• Monobactams (e.g., aztreonam) are beta-lactam antibiotics with activity primarily against Gram-negative bacteria.

Glycopeptides

• Vancomycin inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan precursors.
• It is primarily active against Gram-positive bacteria, including MRSA.
• Resistance to vancomycin is increasing and it is mediated by altered peptidoglycan precursors (e.g., D-Ala-D-Lac).

Tetracyclines

• Tetracyclines (e.g., tetracycline, doxycycline, minocycline) inhibit protein synthesis by binding to the 30S ribosomal subunit.
• They have a broad spectrum of activity, including activity against Gram-positive, Gram-negative, and atypical bacteria.
• Resistance to tetracyclines is common.

Macrolides

• Macrolides (e.g., erythromycin, azithromycin, clarithromycin) inhibit protein synthesis by binding to the 50S ribosomal subunit.
• They are active against many Gram-positive bacteria and some Gram-negative bacteria, as well as atypical bacteria.
• Macrolide resistance is an increasing concern.

Aminoglycosides

• Aminoglycosides (e.g., gentamicin, tobramycin, amikacin) inhibit protein synthesis by binding to the 30S ribosomal subunit.
• They are primarily active against aerobic Gram-negative bacteria.
• Aminoglycosides can cause nephrotoxicity and ototoxicity.
• Therapeutic drug monitoring is often used to optimize aminoglycoside dosing.

Fluoroquinolones

• Fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin) inhibit DNA gyrase and topoisomerase IV, enzymes essential for DNA replication.
• They have a broad spectrum of activity, including activity against Gram-positive and Gram-negative bacteria.
• Fluoroquinolone resistance is increasing.
• Fluoroquinolones have been associated with tendinitis and tendon rupture.

Sulfonamides and Trimethoprim

• Sulfonamides (e.g., sulfamethoxazole) inhibit dihydropteroate synthetase, an enzyme involved in folate synthesis.
• Trimethoprim inhibits dihydrofolate reductase, another enzyme involved in folate synthesis.
• The combination of trimethoprim and sulfamethoxazole (TMP-SMX) has synergistic activity.

Polymyxins

• Polymyxins (e.g., polymyxin B, colistin) disrupt bacterial cell membranes.
• They are primarily active against Gram-negative bacteria, including multidrug-resistant organisms.
• Polymyxins can cause nephrotoxicity and neurotoxicity.

Nitroimidazoles

• Nitroimidazoles (e.g. metronidazole) are activated in anaerobic bacteria and protozoa and they form cytotoxic products that damage DNA
• Effective against anaerobic bacterial infections