A REVIEW ON STRUCTURAL OPTIMIZATION OF BETALACTAM ANTIBIOTICS AND DEVELOPMENT OF ?ETALACTAMASE INHIBITORS AGAINST ESBL-MEDIATED RESISTANCE

Abstract

Extended-Spectrum ?-Lactamase (ESBL)-mediated antimicrobial resistance has become a major challenge in treating Gram-negative bacterial infections by reducing the efficacy of ?-lactam antibiotics. This review evaluates the structural modification strategies of ?-lactam antibiotics and the development of next-generation ?-lactamase inhibitors (BLIs) to restore antibacterial activity against ESBL-producing bacteria. A structured literature search was conducted in PubMed, ScienceDirect, and Google Scholar, covering publications from 2015 to 2025. Of the 305 records identified, 32 studies met the inclusion criteria and were analyzed. Four major structural modification strategies have been identified: C7 and C3 side-chain modification of cephalosporins, introduction of the 7?-methoxy group, carbapenem-inspired steric shielding, and siderophore conjugation. This review also highlights two major classes of next-generation BLIs: diazabicyclooctane (DBO) inhibitors and boronic acid derivatives. Structure–activity relationship (SAR) analysis indicates that these approaches improve resistance to ESBL-mediated hydrolysis via distinct mechanisms. Combination therapies, particularly ?-lactam–DBO combinations and cefiderocol, exhibit enhanced activity against multidrug-resistant ESBL-producing bacteria. Overall, SAR-guided structural modifications and BLI development provide a strong scientific foundation for the rational design of more effective antimicrobial agents against ESBL-producing pathogens. Keywords: Extended-Spectrum ?-Lactamase (ESBL); functional group modification; ?-lactam; structure-activity relationship; ?-Lactamase inhibitor