A d-Phenylalanine-Benzoxazole Derivative Reveals the Role of the Essential Enzyme Rv3603c in the Pantothenate Biosynthetic Pathway of Mycobacterium tuberculosis .

Autor: Pepi MJ; Graduate Program in Chemistry, Brandeis University, Waltham 02453, Massachusetts, United States., Chacko S; Department of Biology, Brandeis University, Waltham 02453, Massachusetts, United States., Marqus GM; Graduate Program in Chemistry, Brandeis University, Waltham 02453, Massachusetts, United States., Singh V; Drug Discovery and Development Centre (H3D), and South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa., Wang Z; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York 10065, New York, United States., Planck K; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York 10065, New York, United States., Cullinane RT; Department of Biology, Brandeis University, Waltham 02453, Massachusetts, United States., Meka PN; Department of Biology, Brandeis University, Waltham 02453, Massachusetts, United States., Gollapalli DR; Department of Biology, Brandeis University, Waltham 02453, Massachusetts, United States., Ioerger TR; Department of Computer Science and Engineering, Texas A&M University, College Station 77843, Texas, United States., Rhee KY; Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York 10065, New York, United States., Cuny GD; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston 77204, Texas, United States., Boshoff HIM; Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda 20892, Maryland, United States., Hedstrom L; Department of Biology, Brandeis University, Waltham 02453, Massachusetts, United States.; Department of Chemistry, Brandeis University, Waltham 02453, Massachusetts, United States.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2022 Feb 11; Vol. 8 (2), pp. 330-342. Date of Electronic Publication: 2022 Jan 11.
DOI: 10.1021/acsinfecdis.1c00461
Abstrakt: New drugs and new targets are urgently needed to treat tuberculosis. We discovered that d-phenylalanine-benzoxazole Q112 displays potent antibacterial activity against Mycobacterium tuberculosis ( Mtb ) in multiple media and in macrophage infections. A metabolomic profiling indicates that Q112 has a unique mechanism of action. Q112 perturbs the essential pantothenate/coenzyme A biosynthetic pathway, depleting pantoate while increasing ketopantoate, as would be expected if ketopantoate reductase (KPR) were inhibited. We searched for alternative KPRs, since the enzyme annotated as PanE KPR is not essential in Mtb . The ketol-acid reductoisomerase IlvC catalyzes the KPR reaction in the close Mtb relative Corynebacterium glutamicum , but Mtb IlvC does not display KPR activity. We identified the essential protein Rv3603c as an orthologue of PanG KPR and demonstrated that a purified recombinant Rv3603c has KPR activity. Q112 inhibits Rv3603c, explaining the metabolomic changes. Surprisingly, pantothenate does not rescue Q112 -treated bacteria, indicating that Q112 has an additional target(s). Q112 -resistant strains contain loss-of-function mutations in the twin arginine translocase TatABC, further underscoring Q112 's unique mechanism of action. Loss of TatABC causes a severe fitness deficit attributed to changes in nutrient uptake, suggesting that Q112 resistance may derive from a decrease in uptake.
Databáze: MEDLINE
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