Small-molecule strategies to combat antibiotic resistance: mechanisms, modifications, and contemporary approaches

Antibiotic resistance poses a formidable threat to human health, representing a critical challenge that demands urgent attention. Without decisive feat, we confront the alarming prospect of a world where effective antibiotics are no longer available. Bacteria employ various mechanisms to elude antibiotics, including modifying antibiotic targets, utilizing efflux pumps to avoid antibiotics, and inactivating antibiotics. This review focuses on small-molecule-based approaches to overcoming resistance, with emphasis on chemical adjuvants (such as β-lactamase inhibitors, efflux pump inhibitors, and membrane permeabilizers), synergistic combination therapies, repurposed non-antibiotic drugs, and structural modifications of known antibiotics like ciprofloxacin. We critically analyze structure-activity relationships (SAR), biochemical mechanisms, and clinical barriers associated with each strategy. By addressing antibiotic resistance, we aim to fortify our ability to combat bacterial infections effectively and sustain the efficacy of existing antibiotics in the face of evolving resistance.