Rv0684/fusA1, an Essential Gene, Is the Target of Fusidic Acid and Its Derivatives in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health concern given the increase in multiple forms of drug-resistant TB. This underscores the importance of a continuous pipeline of new anti-TB agents. Drug repurposing has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, is one such candidate for repurposing. The present study aimed to understand the mechanism of action of FA and its selected analogs in M. tuberculosis. By using chemical biology and genetics, we identified elongation factor G as the target of FA in M. tuberculosis. We showed essentiality of its encoding gene fusA1 in M. tuberculosis by demonstrating that the transcriptional silencing of fusA1 is bactericidal in vitro and in macrophages. Thus, this work validated a novel drug target FusA1 in M. tuberculosis.

Extraintestinal Pathogenic Escherichia coli Utilizes Surface-Located Elongation Factor G to Acquire Iron from Holo-Transferrin

“…EFG is typically a GTPase involved in protein synthesis ( 48 ). In addition, EFG is the target of the antibiotic fusidic acid, mediating the resistance of bacteria to fusidic acid ( 49 – 51 ). The novel moonlighting role of EFG bound with holo-TF was revealed in this study.…”

The implication of Mycobacterium tuberculosis-mediated metabolism of targeted xenobiotics

“…In addition, the C-21 aryl ester 62 was not metabolized to the free acid; 59 is in clinical use against Gram-positive infections, including methicillin-resistant Staphylococcus aureus 33 . In Mtb , 59 targets an essential elongation factor, G , which is crucial for protein translation 34 . Despite 58 showing improved absorption and tissue distribution in pharmacokinetic and organ distribution experiments 32 , preclinical development of fusidic acid as an anti-TB drug has been hampered as a pharmacology proof-of-concept study in a mouse TB infection model showed rodent-mediated metabolism to yield inactive 60 .…”

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

“…This resulted in the cidality of Mtb both in vitro and in macrophages, confirming FusA1 as a novel, chemically tractable, and vulnerable target in Mtb . 41 Owing to the attractiveness of drug repositioning and repurposing approaches, our efforts are continuing in this direction.…”

“…To validate FusA1 as a novel drug target in Mtb , we also tested the viability of fusA1 conditional knockdown upon fusA1 silencing. This resulted in the cidality of Mtb both in vitro and in macrophages, confirming FusA1 as a novel, chemically tractable, and vulnerable target in Mtb . Owing to the attractiveness of drug repositioning and repurposing approaches, our efforts are continuing in this direction.…”