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Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
Bryan Berube1,2, Aditi Deshpande1, Amala Bhagwat1
1Center for Global Infectious Disease, Seattle Children's Research Institute, Seattle, WA, USA.
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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