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Cell Chem Biol. 2016 Feb 18;23(2):290-298. doi: 10.1016/j.chembiol.2016.01.003. Epub 2016 Feb 4.

Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence.

Author information

1
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109, USA.
2
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
3
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA.
4
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. Electronic address: aaron.wright@pnnl.gov.
5
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA. Electronic address: christoph.grundner@cidresearch.org.

Abstract

The transition from replication to non-replication underlies much of Mycobacterium tuberculosis (Mtb) pathogenesis, as non- or slowly replicating Mtb are responsible for persistence and poor treatment outcomes. Therapeutic targeting of non-replicating populations is a priority for tuberculosis treatment, but few drug targets in non-replicating Mtb are currently known. Here, we directly measured the activity of the highly diverse and druggable serine hydrolases (SHs) during active replication and non-replication using activity-based proteomics. We predict SH activity for 78 proteins, including 27 proteins with unknown function, and identify 37 SHs that remain active in the absence of replication, providing a set of candidate persistence targets. Non-replication was associated with major shifts in SH activity. These activity changes were largely independent of SH abundance, indicating extensive post-translational regulation of SHs. By probing a large cross-section of druggable Mtb enzyme space during replication and non-replication, we identify new SHs and suggest new persistence targets.

PMID:
26853625
PMCID:
PMC4803444
DOI:
10.1016/j.chembiol.2016.01.003
[Indexed for MEDLINE]
Free PMC Article

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