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Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor

Berube, B.; Deshpande, A.; Bhagwat, A.; Parish, T.

2023-02-23 microbiology
10.1101/2023.02.22.529622 bioRxiv
Show abstract

Indolcarboxamides are a promising series of anti-tubercular agents which target Mycobacterium tuberculosis MmpL3, the exporter of trehalose monomycolate, a key cell wall component. We determined the kill kinetics of the lead indolcarboxamide NITD-349 and determined that while kill was rapid against low density cultures, bactericidal activity was inoculum-dependent. A combination of NITD-349 with isoniazid (which inhibits mycolate synthesis) had an increased kill rate; this combination prevented the appearance of resistant mutants, even at higher inocula.

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