Antibiotic resistance is the ability of bacteria to withstand the effects of antimicrobial drugs that would otherwise kill them or inhibit their growth. Resistance can be intrinsic (naturally present) or acquired through mutation or horizontal gene transfer.

Enzymatic Inactivation

1. Beta-lactamases hydrolyze the beta-lactam ring of penicillins, cephalosporins, and carbapenems. Examples include TEM-1, SHV-1, and extended-spectrum beta-lactamases (ESBLs).
2. Aminoglycoside-modifying enzymes transfer acetyl, phosphoryl, or adenyl groups to aminoglycosides, reducing ribosome binding. Types include AACs, APHs, and AADs.
3. Chloramphenicol acetyltransferase (CAT) inactivates chloramphenicol by acetylation, preventing protein synthesis inhibition.

Target Modification

1. Mutations in penicillin-binding proteins (PBPs) reduce beta-lactam affinity. MRSA carries mecA encoding PBP2a with low beta-lactam binding.
2. Mutations in DNA gyrase (gyrA) and topoisomerase IV (parC) confer quinolone resistance by altering drug target sites.
3. Methylation of 23S rRNA (erm genes) prevents macrolide, lincosamide, and streptogramin B (MLSB) binding.
4. Mutations in ribosomal proteins or 16S rRNA confer resistance to aminoglycosides (e.g., rpsL mutations in Mycobacterium tuberculosis).

Efflux Pumps

1. Efflux pumps actively export antibiotics from the cell, reducing intracellular concentrations. They are classified into five families: MFS, ABC, RND, SMR, and MATE.
2. RND pumps (e.g., AcrAB-TolC in E. coli) are tripartite systems spanning both membranes of Gram-negative bacteria and export multiple drug classes.
3. Overexpression of efflux pump genes (e.g., mexAB-oprM in Pseudomonas aeruginosa) contributes to multidrug resistance.

Reduced Permeability

1. Gram-negative bacteria limit antibiotic entry through porin channels in the outer membrane. Loss or downregulation of porins (OmpF, OmpC) reduces influx.
2. Changes in lipopolysaccharide (LPS) structure can reduce binding of polymyxins and aminoglycosides.
3. Biofilm formation creates a physical barrier that limits antibiotic penetration and creates microenvironments with reduced metabolic activity.

Horizontal Gene Transfer

1. Conjugation transfers resistance genes on plasmids or transposons between bacteria, even across species boundaries.
2. Transformation allows uptake of free DNA containing resistance genes from the environment.
3. Transduction by bacteriophages can transfer resistance genes between bacterial strains.

Clinical Implications

1. Multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) pathogens are increasingly common.
2. ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species) are leading causes of healthcare-associated infections.
3. Antimicrobial stewardship programs aim to optimize antibiotic use and slow resistance development.