Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor

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.