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Ghodousi, A.* ; Iannucci, I.* ; Saluzzo, F.* ; Dreisbach, J.* ; Mirold-Mei, S.* ; Hoelscher, M. ; Cirillo, D.M.*

Low-level BTZ-043 resistance in Mycobacterium tuberculosis and cross-resistance to bedaquiline and clofazimine.

IJTLD Open 2, 604 - 609 (2025)
Publ. Version/Full Text Research data DOI PMC
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BACKGROUND: Multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis complex (MTBC) remain a significant global health challenge. This study investigates resistance mechanisms to BTZ-043, a novel decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) inhibitor, and its potential cross-resistance with bedaquiline (BDQ) and clofazimine (CFZ). METHODS: BTZ-043-resistant mutants were generated in M. tuberculosis H37Rv by serial exposure to escalating drug concentrations. Minimum inhibitory concentrations (MICs) for BTZ-043 were determined for 130 wild-type strains, including 60 H37Rv independent cultures and 70 diverse clinical isolates, plus 33 non-wild-type clinical strains with known BDQ susceptibility. MICs were correlated with whole-genome sequencing (WGS) data to identify genetic factors underlying resistance. RESULTS: The MIC distribution for clinical MTBC strains was similar to the reference strain, with a mode of 0.002 μg/mL. WGS of resistant mutants revealed mutations in dprE1 and Rv0678. Rv0678 and dprE1 mutations resulted in 4- to 8-fold and >1,000-fold increase in MIC compared with the reference mode, respectively. Sequential clinical strains from BDQ-treated patients showed increased MICs and Rv0678 mutations, indicating low-level cross-resistance. However, Rv0678 mutations in BDQ-susceptible strains did not affect BTZ-043 MICs. CONCLUSION: Rv0678 mutations confer low-level cross-resistance to BTZ-043, BDQ, and CFZ, with variable effects on susceptibility. These findings highlight the complexity of resistance mechanisms and the need for ongoing surveillance and early resistance assessments in drug development.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Bedaquiline ; Clofazimine
ISSN (print) / ISBN 3005-7590
e-ISSN 3005-7590
Journal IJTLD Open
Quellenangaben Volume: 2, Issue: 10, Pages: 604 - 609 Article Number: , Supplement: ,
Publisher International Union Against Tuberculosis and Lung Disease
Reviewing status Peer reviewed
Institute(s) Research Unit Global Health (UGH)