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University of North Carolina at Chapel Hill

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Proc. Natl. Acad. Sci. USA, April 5, 2022,119 (15) e2201632119 | https://doi.org/10.1073/pnas.2201632119 Chemical–genetic interaction mapping links carbon metabolism and cell wall structure to tuberculosis drug efficacy

Eun-Ik Koh^a, Peter O. Oluoch^a, Nadine Ruecker^b, Megan K. Proulx^a, Vijay Soni^b, Kenan C. Murphy^a, Kadamba Papavinasasundaram^a, Charlotte J. Reames^a, Carolina Trujillo^b, Anisha Zaveri^b, Matthew D. Zimmerman^c, Roshanak Aslebagh^d,e, Richard E. Baker^a, Scott A. Shaffer^d,e, Kristine M. Guinnf, Michael Fitzgerald^g, Veronique Dartois^c,h, Sabine Ehrt^b, Deborah T. Hung^g,i,j, Thomas R. Ioerger^k, Eric J. Rubin^f, Kyu Y. Rhee^b, Dirk Schnappinger^b, and Christopher M. Sassetti^a,1

^aDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655; ^bDepartment of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065; ^cCenter for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110; ^dDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655; ^eMass Spectrometry Facility, University of Massachusetts Medical School, Shrewsbury, MA 01545; ^fDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115; ^gBroad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142; ^hDepartment of Medical Sciences, Hackensack School of Medicine, Nutley, NJ 07110; ⁱCenter for Computation and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; ^jDepartment of Genetics, Harvard Medical School, Boston, MA 02114; and ^kDepartment of Computer Science and Engineering, Texas A&M University, College Station, TX 77840

¹To whom correspondence may be addressed.

Abstract

Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug–drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilized conditional Mtb knockdown mutants of essential genes as an experimentally tractable surrogate for drug treatment and probe the relationship between Mtb carbon metabolism and chemical–genetic interactions (CGIs). We examined the antitubercular drugs isoniazid, rifampicin, and moxifloxacin and found that CGIs are differentially responsive to the metabolic state, defining both environment-independent and -dependent interactions. Specifically, growth on the in vivo–relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGIs could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of chemical–genetic–environmental interactions that can be used to optimize drug–drug interactions, as well as provide a framework for understanding in vitro correlates of in vivo efficacy.

논문정보

형식Research article
게재일2022년 04월 (BRIC 등록일 2022-04-20)
연구진국외 연구진
분야 생명과학 > 미생물학

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