Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor

Bryan Berube; Aditi Deshpande; Amala Bhagwat; Tanya Parish

doi:10.1099/mic.0.001345

Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor

Bryan Berube
, Aditi Deshpande
, Amala Bhagwat
, Tanya Parish

Seattle Children's Research Institute
Infectious Disease Research Institute
Center for Global Infectious Disease
TB Discovery Research
University of Washington

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	001345
Journal	Microbiology (United Kingdom)
Volume	169
Issue number	6
DOIs	https://doi.org/10.1099/mic.0.001345
Publication status	Published - 19 Jun 2023
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

anti-tubercular
bactericidal activity
cell-wall inhibitor
tuberculosis drug discovery

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10.1099/mic.0.001345

Cite this

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title = "Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor",

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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AU - Berube, Bryan

AU - Deshpande, Aditi

AU - Bhagwat, Amala

AU - Parish, Tanya

PY - 2023/6/19

Y1 - 2023/6/19

N2 - 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.

AB - 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.

KW - anti-tubercular

KW - bactericidal activity

KW - cell-wall inhibitor

KW - tuberculosis drug discovery

U2 - 10.1099/mic.0.001345

DO - 10.1099/mic.0.001345

M3 - Article

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AN - SCOPUS:85162659780

SN - 1350-0872

VL - 169

JO - Microbiology (United Kingdom)

JF - Microbiology (United Kingdom)

IS - 6

M1 - 001345

ER -

Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor

Abstract

UN SDGs

Keywords

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