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<div><p>Drug-resistant tuberculosis is a pressing global health issue that requires the development of new drugs or the identification of new therapeutic targets. The ESX-3 secretion system is essential for the <i>Mycobacterium tuberculosis</i> growth and plays a role in iron...
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2025
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| Summary: | <div><p>Drug-resistant tuberculosis is a pressing global health issue that requires the development of new drugs or the identification of new therapeutic targets. The ESX-3 secretion system is essential for the <i>Mycobacterium tuberculosis</i> growth and plays a role in iron/zinc homeostasis and virulence. The aim of this study was to evaluate the quaternary interface of EccD3, a component of the ESX-3 secretion system, and to evaluate the association of an <i>eccD3</i> mutant with drug resistance. The molecular structures of EccD3 protein and other ESX-3 secretion system proteins of the <i>M. tuberculosis</i> were predicted based in homology with the <i>Mycolicibacterium smegmatis</i> tertiary protein structures. According to the <i>in silico</i> results, selamectin, avermectin, ivermectin, and moxidectin were selected as prospective drugs. Selamectin and moxidectin had favorable ΔG values for the EccB3 and EccD3 dimer interfaces, whereas the ESX-3 Protomer 1 interface had the best ΔG + with avermectin, ivermectin, and moxidectin. Furthermore, ivermectin susceptibility increased when the <i>eccD3</i> gene was inhibited using CRISPRi in <i>M. smegmatis</i>. Blockage of EccD3 increased the ivermectin action, but the modest changes observed may be explained by the compensatory mechanisms or other ivermectin targets in absence of this Esx3 component. Further <i>in vitro</i> and preclinical studies are required to validate our findings.</p></div> |
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