Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis.

Autor:	Bosch B; Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY 10065, USA., DeJesus MA; Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY 10065, USA., Poulton NC; Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY 10065, USA., Zhang W; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY 10065, USA., Engelhart CA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Zaveri A; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Lavalette S; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Ruecker N; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Trujillo C; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Wallach JB; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Li S; Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY 10065, USA., Ehrt S; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA., Chait BT; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY 10065, USA., Schnappinger D; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: dis2003@med.cornell.edu., Rock JM; Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: rock@rockefeller.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Aug 19; Vol. 184 (17), pp. 4579-4592.e24. Date of Electronic Publication: 2021 Jul 22.
DOI:	10.1016/j.cell.2021.06.033
Abstrakt:	Antibacterial agents target the products of essential genes but rarely achieve complete target inhibition. Thus, the all-or-none definition of essentiality afforded by traditional genetic approaches fails to discern the most attractive bacterial targets: those whose incomplete inhibition results in major fitness costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait that relates the magnitude of gene inhibition to the effect on bacterial fitness. We developed a CRISPR interference-based functional genomics method to systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and monitor fitness outcomes. We identified highly vulnerable genes in various processes, including novel targets unexplored for drug discovery. Equally important, we identified invulnerable essential genes, potentially explaining failed drug discovery efforts. Comparison of vulnerability between the reference and a hypervirulent Mtb isolate revealed incomplete conservation of vulnerability and that differential vulnerability can predict differential antibacterial susceptibility. Our results quantitatively redefine essential bacterial processes and identify high-value targets for drug development. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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