Antibiotics & Resistance

1. Antibiotic Targets

Effective antibiotics exploit features of bacterial cells absent from eukaryotes. The five main targets:

• Cell-wall biosynthesis — β-lactams (penicillins, cephalosporins, carbapenems), glycopeptides (vancomycin), polymyxins (Gram-negative outer membrane).
• Protein synthesis (50S subunit) — macrolides (erythromycin, azithromycin), chloramphenicol, oxazolidinones (linezolid).
• Protein synthesis (30S subunit) — aminoglycosides (gentamicin, streptomycin), tetracyclines, glycylcyclines.
• DNA replication / repair — fluoroquinolones (ciprofloxacin) target gyrase and topoisomerase IV; rifampin targets RNA polymerase.
• Folate synthesis — sulphonamides + trimethoprim (act on DHPS and DHFR, blocking tetrahydrofolate synthesis).

2. The β-Lactam Story

The strained four-member β-lactam ring is a structural mimic of the D-Ala−D-Ala terminus of peptidoglycan precursors. It acylates the active-site serine of penicillin-binding proteins (PBPs), inactivating them and arresting cell-wall synthesis. The cell continues to grow, the wall fails, and lysis follows.

Generations of β-lactams (penicillin G → ampicillin → cephalosporins → carbapenems) progressively widened spectrum and overcame specific bacterial resistance mechanisms. Combinations with β-lactamase inhibitors (clavulanic acid, tazobactam, avibactam) restore activity against resistant strains. Carbapenems remain the last-line β-lactams — and carbapenem resistance is now spreading.

3. Resistance Mechanisms

Bacteria evolve resistance by four broad strategies:

• Drug inactivation — β-lactamases hydrolyse the β-lactam ring (TEM-1, CTX-M, NDM-1 “New Delhi metallo-β-lactamase”); aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases).
• Target modification — PBP2a in MRSA (low affinity for β-lactams); ribosomal methylation by Erm (macrolide resistance); D-Ala−D-Ala → D-Ala−D-Lac in vancomycin-resistant Enterococcus (VRE) reduces vancomycin affinity 1000-fold.
• Reduced uptake — loss of OmpF/OmpC porins in Gram-negatives; LPS modification reduces colistin uptake.
• Active efflux — multidrug efflux pumps (AcrAB-TolC in E. coli; MexAB-OprM in Pseudomonas) pump out a broad range of drugs across both membranes.

Resistance genes spread via conjugative plasmids, transposons, and integrons. The mobile resistome can be transferred across species in a single conjugation event — the mcr-1 colistin resistance gene appeared on plasmids in China in 2015 and spread globally within months.

4. ESKAPE Pathogens

The acronym ESKAPE labels the six pathogens responsible for most multidrug-resistant hospital infections:

• Enterococcus faecium (vancomycin)
• Staphylococcus aureus (MRSA, VRSA)
• Klebsiella pneumoniae (ESBL, KPC, NDM)
• Acinetobacter baumannii (carbapenem)
• Pseudomonas aeruginosa (efflux, biofilms)
• Enterobacter spp.

The WHO maintains a priority pathogen list to guide R&D. The pipeline is thin: fewer than 10 truly novel-mechanism antibiotics have entered the clinic in the last two decades. Recently, teixobactin (Lewis 2015, found by reviving uncultured soil bacteria) and AI-discovered candidates such as halicin (Stokes 2020) point to new screening strategies.

5. Tolerance vs Resistance

Resistance is genetically encoded survival in the presence of antibiotic. Tolerance is a slower-killing phenotype, often physiological rather than genetic, and includes:

• Persisters — rare (1 in 10⁵), dormant cells that survive antibiotic exposure and re-grow after removal. Drive relapse in tuberculosis and chronic infections.
• Biofilm tolerance — matrix-protected, slow-growing biofilm cells survive concentrations 100× planktonic MIC.
• Heteroresistance — subpopulations within an isolate that grow at otherwise-inhibitory concentrations.

Persister biology was opened up by Kim Lewis and colleagues. The mechanism is still debated — the (p)ppGpp stringent response, toxin-antitoxin system activation, and stochastic gene expression all contribute.

6. Beyond Small Molecules

• Phage therapy — bacteriophages as bacteriocidal agents. Used clinically in the former Soviet Union for decades; revisited in the West in compassionate-use settings (Tom Patterson’s 2016 cure of multidrug-resistant Acinetobacter).
• Antibodies — bezlotoxumab against C. difficile toxin B is FDA-approved.
• Anti-virulence drugs — quorum-quenching, toxin neutralisation; lower selection pressure for resistance.
• Microbiome restoration — faecal microbiota transplant (FMT) for recurrent C. difficile infection — the only approved “ecological” antibacterial therapy.