Antibiotics and antibiotic resistance race: a chronicle of antibiotic discovery against Gram-negative bacteria during 2001-2020: way forward

Abstract

The continuous evolutionary race between antibacterial innovation and antimicrobial resistance (AMR) has become one of the greatest challenges in the management of Gram-negative bacterial infections. Although numerous antibiotics and β-lact- am–β-lactamase inhibitor combinations have been introduced since 2000, their clinical utility has been progressively eroded by the rapid emergence and global dissemination of resistance mechanisms, including carbapenemase production, reduced outer membrane permeability, multidrug efflux, target modification, and antibiotic-inactivating enzymes. This review pro- vides a chronological and mechanistic overview of anti-Gram-negative antibiotic development over the past two decades while examining the parallel evolution of bacterial resistance that has limited the therapeutic lifespan of both established and newly approved agents. We critically discuss the mechanisms of action, antibacterial spectrum, pharmacological characteris- tics, clinical utility, and resistance determinants of recently approved antibiotics, with particular emphasis on therapeutic in- novations that overcome conventional resistance barriers, including advanced β-lactam–β-lactamase inhibitor combinations, the siderophore cephalosporin cefiderocol, next-generation tetracyclines, aminoglycosides, and novel bacterial topoisomer- ase inhibitors. Emerging therapeutic strategies, including investigational antibacterial agents, artificial intelligence-assisted antibiotic discovery, bacteriophage therapy, and CRISPR-based antimicrobial approaches, are also reviewed as potential solutions to the growing challenge of multidrug-resistant Gram-negative pathogens. Collectively, these advances illustrate that successful antibiotic development increasingly depends on innovative target engagement, improved bacterial uptake, and resistance-informed drug design rather than incremental modification of existing scaffolds alone. Ultimately, preserv- ing the clinical effectiveness of new antibiotics will require the integration of antimicrobial stewardship, rapid diagnostics, genomic surveillance, and mechanism-guided drug development to slow the continuing evolutionary arms race between bacterial adaptation and therapeutic innovation.