Strategy-based design for the identification of next generation β-lactam antibiotics that evade resistance from Gram-negative pathogens

INTRODUCTION: β-Lactam antibiotics have defined antibacterial chemotherapy for over eight decades and remain indispensable for the treatment of bacterial infections. Despite their clinical success, escalating antimicrobial resistance, particularly among Gram-negative pathogens, continues to impair their efficacy. This challenge has shifted the field from scaffold discovery to strategy-driven innovation aimed at overcoming firmly established resistance mechanisms. AREAS COVERED: This review summarizes the current landscape of β-lactam antibiotic discovery and development, with particular emphasis on strategies designed to overcome resistance in Gram-negative pathogens. The authors discuss recent advances in β-lactam antibiotics and β-lactamase inhibitors, including clinically approved agents, compounds in late-stage clinical development, and emerging approaches targeting resistant pathogens. Furthermore, they highlight the key molecular determinants of resistance that undermine current β-lactam therapies and provide perspectives on emerging opportunities for the development of next-generation β-lactam antibiotics and β-lactamase inhibitors designed to retain activity against multidrug-resistant Gram-negative pathogens. EXPERT OPINION: Strategies to overcome resistance in Gram-negative bacteria have established a robust foundation for the development of next-generation β-lactam antibiotics. The integration of broad-spectrum β-lactamase inhibitors, novel PBP-targeting chemotypes, enhanced outer-membrane permeation, siderophore-mediated drug delivery, and structure-guided medicinal chemistry is expected to produce β-lactam agents with improved efficacy against multidrug-resistant Gram-negative pathogens.