An integrated approach to anti-virulence drug discovery: targeting salicylate synthase in mycobacterial infections

Tuberculosis (TB) remains the leading cause of mortality from a single infectious agent, despite sustained global efforts to improve therapeutic strategies [1]. The rise of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains further highlights the urgent need for new treatments based on innovative mechanisms of action. In this context, we have developed an anti-virulence approach targeting the salicylate synthase of Mtb (MbtI), a key enzyme involved in the biosynthesis of myobactins and carboxymycobactins, iron-chelating molecules pivotal for mycobacterial survival and pathogenicity during infection [2]. Importantly, the absence of MbtI homologues in humans supports its potential as a selective therapeutic target. A structure-guided strategy, supported by co-crystal structures of MbtI in complex with lead compounds, enabled the identification and optimization of small-molecule inhibitors displaying potent enzymatic activity and antimycobacterial effects under iron-limited conditions [3]. To address intracellular delivery challenges, prodrugs of these compounds were encapsulated in poly(2-(methacryloyloxy)ethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes. These nanocarriers exploit scavenger receptor-mediated uptake to preferentially target infected macrophages and promote cytosolic release of the payload, thereby reaching the intracellular niche of Mtb [4]. Overall, this integrated approach, spanning hit identification, structure-based optimization, and targeted intracellular delivery, supports the potential of MbtI inhibition as an anti-virulence strategy for TB and provides a foundation for further in vivo evaluation.