Exploring FabH inhibitors for antimicrobial therapy: medicinal chemistry, synthetic approaches, and SAR evaluation

The rapid and widespread rise of antibiotic resistance worldwide poses a serious threat to public health, affecting healthcare workers and researchers. This issue is worsened by the emergence of multidrug-resistant and extensively drug-resistant strains of microorganisms, which has significantly hampered the therapeutic utility of currently used antibiotics. The misuse of antibiotics across the globe has only worsened the situation and created an urgent need for discovery of new antibacterial targets. In this context, the bacterial fatty acid biosynthesis pathway, especially fatty acid synthase III (FabH), represents one of the most desirable sources of underutilized targets for developing new antibacterial agents. FabH is involved in the biosynthesis of fatty acids in plants and animals. The inhibition of FabH emerged as a potential drug development approach for designing and discovering new antibacterial agents. However, not a single drug molecule has reached to market due to the non-availability of selective inhibitors. In recent years, various research groups have extensively explored the therapeutic potential of FabH inhibitors to develop new antibacterial agents. However, the medicinal perspective and recent advances of this class of high-utility ligands have not been well documented. The present review is a comprehensive compilation of recent progress in the medicinal chemistry of FabH inhibitors as antibacterial agents. The biological perspective, structural-activity relationships, and in silico studies are discussed in the manuscript. We hope this review will be a useful guiding tool for the research community to develop potent and effective FabH inhibitors.