Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor

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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...

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Autores principales: Berube, Bryan, Deshpande, Aditi, Bhagwat, Amala, Parish, Tanya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980077/
https://www.ncbi.nlm.nih.gov/pubmed/36865226
http://dx.doi.org/10.1101/2023.02.22.529622
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author Berube, Bryan
Deshpande, Aditi
Bhagwat, Amala
Parish, Tanya
author_facet Berube, Bryan
Deshpande, Aditi
Bhagwat, Amala
Parish, Tanya
author_sort Berube, Bryan
collection PubMed
description 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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spelling pubmed-99800772023-03-03 Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor Berube, Bryan Deshpande, Aditi Bhagwat, Amala Parish, Tanya bioRxiv Article 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. Cold Spring Harbor Laboratory 2023-02-23 /pmc/articles/PMC9980077/ /pubmed/36865226 http://dx.doi.org/10.1101/2023.02.22.529622 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Berube, Bryan
Deshpande, Aditi
Bhagwat, Amala
Parish, Tanya
Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
title Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
title_full Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
title_fullStr Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
title_full_unstemmed Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
title_short Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
title_sort inoculum-dependent bactericidal activity of a mycobacterium tuberculosis mmpl3 inhibitor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980077/
https://www.ncbi.nlm.nih.gov/pubmed/36865226
http://dx.doi.org/10.1101/2023.02.22.529622
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AT bhagwatamala inoculumdependentbactericidalactivityofamycobacteriumtuberculosismmpl3inhibitor
AT parishtanya inoculumdependentbactericidalactivityofamycobacteriumtuberculosismmpl3inhibitor

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