STRUCTURE-GUIDED DESIGN OF BETA-LACTAM ANTIBIOTICS AND BETA-LACTAMASE INHIBITORS AGAINST MULTIDRUG-RESISTANT PATHOGENS

Beta-lactam antibiotics remain essential in treating bacterial infections due to their broad-spectrum efficacy and low toxicity. However, the increasing prevalence of beta-lactamase-mediated resistance, particularly among multidrug-resistant Gram-negative bacteria, undermines their clinical effectiveness. Recent advances in structural modification and new beta-lactamase inhibitors, such as Cefiderocol, Avibactam, Relebactam, and taniborbactam, have shown promising results against resistant pathogens like Carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. Structure-activity relationship (SAR) studies significantly improved antibiotic stability, bacterial membrane penetration, and resistance evasion. Innovative approaches, including monocyclic beta-lactams and siderophore-conjugated antibiotics, further expand therapeutic options. Additionally, targeted modifications against penicillin-binding proteins have enhanced beta-lactam efficacy. Despite these improvements, challenges persist, notably variability in therapeutic drug monitoring (TDM), limited inhibitor spectrums, and rapid resistance emergence. Future research should prioritize developing broad-spectrum, irreversible beta-lactamase inhibitors with optimized pharmacokinetics and minimal adverse effects, to maintain beta-lactams as effective tools against antimicrobial resistance.