Skip to content
1887

Microbiology Society logo Microbiology

Volume 169, Issue 6

Inoculum-dependent bactericidal activity of a MmpL3 inhibitor Open Access

Abstract

Indolcarboxamides are a promising series of anti-tubercular agents, which target 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.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): anti-tubercular , bactericidal activity , cell-wall inhibitor and tuberculosis drug discovery
Funding
This study was supported by the:
  • Bill and Melinda Gates Foundation (Award INV-005585)
    • Principal Award Recipient: TanyaParish
  • Bill and Melinda Gates Foundation (Award OPP1024038)
    • Principal Award Recipient: TanyaParish
  • National Institutes of Health (Award R01AI129360)
    • Principal Award Recipient: TanyaParish
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.001345
2023-06-19
2026-01-19

Metrics

Loading full text...

Full text loading...

/deliver/fulltext/micro/169/6/mic001345.html?itemId=/content/journal/micro/10.1099/mic.0.001345&mimeType=html&fmt=ahah

References

  1. World Health Organization Global tuberculosis report 2022; 2022
  2. Shao M, McNeil M, Cook GM, Lu X. MmpL3 inhibitors as antituberculosis drugs. Eur J Med Chem 2020; 200:112390 [View Article] [PubMed]
     [Google Scholar]
  3. Rao SPS, Lakshminarayana SB, Kondreddi RR, Herve M, Camacho LR et al. Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis. Sci Transl Med 2013; 5:214ra168 [View Article] [PubMed]
     [Google Scholar]
  4. Ollinger J, Bailey MA, Moraski GC, Casey A, Florio S et al. A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis. PLoS One 2013; 8:e60531 [View Article] [PubMed]
     [Google Scholar]
  5. Early J, Alling T. Determination of compound kill kinetics against Mycobacterium tuberculosis. Methods Mol Biol 2015; 1285:269–279 [View Article] [PubMed]
     [Google Scholar]
  6. Sorg RA, Lin L, van Doorn GS, Sorg M, Olson J et al. Collective resistance in microbial communities by intracellular antibiotic deactivation. PLoS Biol 2016; 14:e2000631 [View Article] [PubMed]
     [Google Scholar]
  7. Tan C, Smith RP, Srimani JK, Riccione KA, Prasada S et al. The inoculum effect and band-pass bacterial response to periodic antibiotic treatment. Mol Syst Biol 2012; 8:617 [View Article] [PubMed]
     [Google Scholar]
  8. Diaz-Tang G, Meneses EM, Patel K, Mirkin S, García-Diéguez L et al. Growth productivity as a determinant of the inoculum effect for bactericidal antibiotics. Sci Adv 2022; 8:eadd0924 [View Article] [PubMed]
     [Google Scholar]
/content/journal/micro/10.1099/mic.0.001345
Loading
Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor
Microbiology 169, 001345 (2023); https://doi.org/10.1099/mic.0.001345
/content/journal/micro/10.1099/mic.0.001345
/content/journal/micro/10.1099/mic.0.001345
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An error occurred
Approval was partially successful, following selected items could not be processed due to error