title: Systematic Survey of Serine Hydrolase Activity in Mycobacterium tuberculosis Defines Changes Associated with Persistence.
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.
authors: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109, USA.
authors: Corrie
authors: C
authors: Ortega
authors: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors: Lindsey N
authors: LN
authors: Anderson
authors: 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.
authors: Andrew
authors: A
authors: Frando
authors: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors: Natalie C
authors: NC
authors: Sadler
authors: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109, USA.
authors: Robert W
authors: RW
authors: Brown
authors: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors: Richard D
authors: RD
authors: Smith
authors: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. Electronic address: aaron.wright@pnnl.gov.
authors: Aaron T
authors: AT
authors: Wright
authors: 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.
authors: Christoph
authors: C
authors: Grundner
mesh_terms: D002853:Chromatography, Liquid; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004789:Enzyme Activation; D006867:Hydrolases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D013058:Mass Spectrometry; D009169:Mycobacterium tuberculosis / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D012694:Serine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D012694:Serine; D006867:Hydrolases