Enzyme-driven antimicrobial resistance and advancements in sustainable anti-infective strategies.

Antibiotic resistance is an emerging global issue that has reduced the efficacy of antibiotics for treating life-threatening bacterial infections. Bacterial adaptive enzymatic defense mechanisms allow cells to activate or modify specific enzymes that inactivate antibiotics and support survival under antimicrobial stress. Antibiotics are predominantly inactivated through enzymatic degradation or chemical modification. Most of the β-lactamases, macrolide esterases, tetracycline-modifying enzymes, fosfomycin degrading enzymes, aminoglycoside-modifying enzymes, and other bacterial enzymes chemically modify or degrade the antibiotics making them inactive. This review covers classification and mechanisms of enzyme-mediated resistance and emphasizes the significant enzymes involved in inactivation of various antibiotic classes. It also summarizes recent biotechnological advances to combat antibiotic resistance, including β-lactamase inhibitors, phage therapy, antimicrobial peptides, and CRISPR-Cas9 systems, along with emerging therapeutic approaches and current trends in antibiotic research. A deeper understanding of enzyme-mediated resistance and the cellular intelligence driving bacterial adaptation is crucial for designing effective therapeutic strategies, preserving antibiotic efficacy, and reducing the global burden of resistant infections.