Antibacterial drug discovery: challenges and preclinical promises from synthetic small molecules

Over the past few decades, antibacterial discovery has changed substantially, yet innovation has remained slow despite the growing need for new agents active against multidrug-resistant pathogens. Progress is constrained by scientific hurdles, including target selection, penetration and efflux in bacteria, and the difficulty of translating in vitro activity into in vivo efficacy, as well as persistent economic disincentives. Here, we discuss these challenges and summarise recent advances in the field, with a medicinal chemistry focus on synthetic small molecules that have reached validated-lead or preclinical development and shown in vivo antibacterial efficacy. We also provide an outline of the current clinical pipeline, highlighting areas of innovation and remaining gaps. Our goal is to offer a comprehensive perspective on antibacterial discovery that supports ongoing efforts to strengthen the pipeline in response to antimicrobial resistance.