Repurposing of FDA-Approved Drugs to Disrupt Iron Uptake in Mycobacterium abscessus: Targeting Salicylate Synthase as a Novel Approach

Abstract

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that lead to severe, persistent infections, particularly in immunocompromised or vulnerable individuals. Infection rates are rising worldwide, highlighting NTM as an increasing threat to public health. There are currently no specific drugs, and the recommended regimens are usually ineffective. This scenario underlines the urgent need to develop new strategies to effectively combat these infections in a more innovative way. However, the development of new drugs can be a lengthy process, often taking more than a decade to identify even a single active compound. Among the new strategies that can expedite this process is the repurposing of approved drugs. In this work, we applied this approach to identify compounds inhibiting iron uptake in Mycobacterium abscessus (Mab). Specifically, we studied the targeting of salicylate synthase, an enzyme that plays a crucial role in the biosynthesis of mycobacterial siderophores necessary for iron acquisition. Performing an in silico virtual screening of three databases against the crystal structure of salicylate synthase, we identified 11 potential ligands. Then, in vitro assays on the recombinant enzyme highlighted three competitive inhibitors, namely fostamatinib, esomeprazole, and hydroxystilbamidine. These results confirm the potential of the repurposing approach and pave the way for further experimental validation and optimization of these inhibitors as promising compounds against NTM infections.