Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis.
Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course. Silencing of coaBC was likewise bactericidal in vivo, whether initiated at infection or during either the acute or chronic stages of infection, confirming that CoaBC is required for M. tuberculosis to grow and persist in mice and arguing against significant CoaBC bypass via transport and assimilation of host-derived pantetheine in this animal model. These results provide convincing genetic validation of CoaBC as a new bactericidal drug target.
MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town , Anzio Road, Observatory 7925, South Africa.
Joanna C
JC
Evans
Department of Microbiology and Immunology, Weill Cornell Medical College , New York, New York 10065, United States.
Carolina
C
Trujillo
Department of Microbiology and Immunology, Weill Cornell Medical College , New York, New York 10065, United States.|Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College , New York, New York 10065, United States.
Zhe
Z
Wang
Department of Microbiology and Immunology, Weill Cornell Medical College , New York, New York 10065, United States.|Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College , New York, New York 10065, United States.
Hyungjin
H
Eoh
Department of Microbiology and Immunology, Weill Cornell Medical College , New York, New York 10065, United States.
Sabine
S
Ehrt
Department of Microbiology and Immunology, Weill Cornell Medical College , New York, New York 10065, United States.
Dirk
D
Schnappinger
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health , Bethesda, Maryland 20892, United States.
Helena I M
HI
Boshoff
Department of Microbiology and Immunology, Weill Cornell Medical College , New York, New York 10065, United States.|Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College , New York, New York 10065, United States.
Kyu Y
KY
Rhee
MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town , Anzio Road, Observatory 7925, South Africa.|Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health , Bethesda, Maryland 20892, United States.
Clifton E
CE
Barry
MRC/NHLS/UCT Molecular Mycobacteriology Research Unit & DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town , Anzio Road, Observatory 7925, South Africa.
Valerie
V
Mizrahi
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010453:Peptide Synthases; D003065:Coenzyme A
CoA; CoaBC; drug discovery; pantetheine; tuberculosis
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