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DprE1 inhibitors and bedaquiline combination for the treatment of TB: in vitro effect on MIC of susceptible and resistant M. tuberculosis strains

A Muscetti(1) F Saluzzo(1) A Ghodousi(1) R Sorrentino(1) D M Cirillo(1)

1:San Raffaele Scientific Institute

The efficacy of the new, short regimen, for drug resistant tuberculosis (DR-TB) treatment "BPaLM" is currently threatened by the increasing resistance to bedaquiline (BDQ). Resistance to BDQ is often driven by mutations on Rv0678, a transcriptional repressor that regulates the efflux pump MmpS5-MmpL5. It's reported that DprE1 inhibitors, the latest developed anti-TB drugs, share the same resistance pattern. A systematic review was performed by our group, to identify the molecular bases of DprE1 inhibitors resistance mechanisms. Our analysis underscored the importance of testing drug synergism, particularly for drugs that may share the same resistance mechanism. Accordingly, we developed a checkerboard assay based on the established EUCAST protocol for determining MICs in M. tuberculosis complex. We tested the DprE1 inhibitor BTZ-043 and BDQ or delamanid (DLM) through double serial dilutions, assessing their concentrations individually and in combination to determine individual drug effects as well as synergistic effects. To set our assay, we included 7 crossed dilutions per drug combination (BTZ-043 and DLM 0,004 mg/L±3 dilution, BDQ 0,032 mg/L±3 dilution) all tested against the H37Rv reference strain. Initial findings indicate a MIC shift between the BTZ-043/DLM control combination and the BTZ-043/BDQ combination. As anticipated, there was no evident synergistic effect observed for the BDQ/DLM combination. Whereas, these findings suggest a possible synergistic or additive effect of BDQ and DprE1 inhibitors, in H37Rv strain. Currently, we are in the process of validating these findings on a larger cohort, encompassing both BDQ-resistant any suceptible clinical isolates.

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