Recchia Deborah, Stelitano Giovanni, Egorova Anna, Batisti Biffignandi Gherard, Savková Karin, Kafková Radka, Huszár Stanislav, Marino Cerrato Antonio, Slayden Richard A, Cummings Jason E, Whittel Nicholas, Bauman Allison A, Robertson Gregory T, Rank Laura, Urbina Fabio, Lane Thomas R, Ekins Sean, Riabova Olga, Kazakova Elena, Mikušová Katarína, Sassera Davide, Degiacomi Giulia, Chiarelli Laurent Robert, Makarov Vadim, Pasca Maria Rosalia
Department of Biology and Biotechnology "Lazzaro Spallanzani,", University of Pavia, 27100 Pavia, Italy.
Research Centre of Biotechnology RAS, Moscow 119071, Russia.
ACS Infect Dis. 2025 Apr 11;11(4):986-997. doi: 10.1021/acsinfecdis.4c01030. Epub 2025 Mar 20.
Among the critical priority pathogens listed by the World Health Organization, strains resistant to rifampicin present a significant global threat. Consequently, the study of the mechanisms of resistance to new antitubercular drugs and the discovery of new effective molecules are two crucial points in tuberculosis drug discovery. In this study, we discovered a compound named RCB18350, which is active against growth and exhibits a minimum inhibitory concentration (MIC) of 1.25 μg/mL. It was also effective against multidrug-resistant isolates. We deeply studied the mechanism of resistance/action of RCB18350 by using several approaches. We found that Rv3406, an iron- and α-ketoglutarate-dependent sulfate ester dioxygenase, is capable of metabolizing the compound into its inactive metabolite. This finding highlights the role of this enzyme in the mechanism of resistance to RCB18350.
在世界卫生组织列出的关键优先病原体中，对利福平耐药的菌株构成了重大的全球威胁。因此，研究新型抗结核药物的耐药机制以及发现新的有效分子是结核病药物研发中的两个关键点。在本研究中，我们发现了一种名为RCB18350的化合物，它对生长具有活性，最低抑菌浓度（MIC）为1.25μg/mL。它对多重耐药菌株也有效。我们通过多种方法深入研究了RCB18350的耐药/作用机制。我们发现，Rv3406，一种依赖铁和α-酮戊二酸的硫酸酯双加氧酶，能够将该化合物代谢为无活性的代谢产物。这一发现突出了该酶在对RCB18350耐药机制中的作用。
