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A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicating Mycobacterium tuberculosis

Michael Li, Hiren V. Patel, Armand B. Cognetta III, Trever C. Smith II, Ivy Mallick, Jean-François Cavalier, Stephane Canaan, View ORCID ProfileBree B. Aldridge, Benjamin F. Cravatt, View ORCID ProfileJessica C. Seeliger
doi: https://doi.org/10.1101/2021.04.16.440156
Michael Li
Department of Pharmacological Sciences and Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, U.S.A.
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Hiren V. Patel
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Armand B. Cognetta III
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Trever C. Smith II
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Ivy Mallick
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Jean-François Cavalier
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Stephane Canaan
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Bree B. Aldridge
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Benjamin F. Cravatt
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Jessica C. Seeliger
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  • ORCID record for Jessica C. Seeliger
  • For correspondence: jessica.seeliger@stonybrook.edu
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ABSTRACT

The identification and validation of a small molecule’s targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecule’s targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here we studied the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis (Mtb). After screening ~200 compounds, we focused on two inhibitors active against both exponentially replicating and hypoxia-induced drug-tolerant Mtb that form part of a four-compound structure-activity series. The compound with negligible activity revealed potential false positive targets not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirmed that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings showed that ABPP identifies the targets most likely relevant to a compound’s antibacterial activity.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† Lead Contact: jessica.seeliger{at}stonybrook.edu

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 16, 2021.
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A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicating Mycobacterium tuberculosis
Michael Li, Hiren V. Patel, Armand B. Cognetta III, Trever C. Smith II, Ivy Mallick, Jean-François Cavalier, Stephane Canaan, Bree B. Aldridge, Benjamin F. Cravatt, Jessica C. Seeliger
bioRxiv 2021.04.16.440156; doi: https://doi.org/10.1101/2021.04.16.440156
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A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicating Mycobacterium tuberculosis
Michael Li, Hiren V. Patel, Armand B. Cognetta III, Trever C. Smith II, Ivy Mallick, Jean-François Cavalier, Stephane Canaan, Bree B. Aldridge, Benjamin F. Cravatt, Jessica C. Seeliger
bioRxiv 2021.04.16.440156; doi: https://doi.org/10.1101/2021.04.16.440156

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