Targeting Mycolic Acid Biosynthesis with Cyclic Sulfamates: A New Strategy against <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the deadliest infectious disease globally. Current TB regimens involving multidrug cocktails for ≥4 months with significant side effects leave much to be desired, with the first- and second-line drugs inhibiting only a limited number of bacterial targets. Thus, potent antimycobacterial agents with novel targets and mechanisms of action are urgently needed to overcome these limitations and the emergence of multidrug-resistant strains. To address this need, we tested a panel of cyclic sulfamate (CS) compounds and identified novel chemotypes that exhibit potent and highly selective activity against Mtb. Most importantly, multiple lines of evidence that include whole genome sequencing of spontaneous resistant mutants, cell-wall damage reporter assays, modeling of drug–target interactions, and cell wall lipid profiling support the hypothesis that these compounds kill Mtb by inhibiting KasA. KasA encodes a β-ketoacyl synthase, whose role in elongation of acyl-AcpM chains is required for the biosynthesis of mycolic acids. Despite being well validated as an essential enzyme, KasA is still an underexploited drug target in Mtb. In our work, the unchanged susceptibility of CS-resistant mutants to front-line TB drugs provides further evidence that the CS series of compounds acts via a novel mechanism of action. The knowledge gained in this study about structure–activity relationships will guide future medicinal chemistry optimization of the CS scaffold and evaluation of the in vivo efficacy of this chemical series. If successful, this novel chemotype may serve as the starting point for the development of alternative treatment options for TB.