Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity.
Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity.
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DOI：
10.1021/acsinfecdis.0c00904
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发表时间：
2021-06-11
影响因子：
5.3
通讯作者：
Mizrahi V
中科院分区：
文献类型：
--
作者：
Evans JC;Murugesan D;Post JM;Mendes V;Wang Z;Nahiyaan N;Lynch SL;Thompson S;Green SR;Ray PC;Hess J;Spry C;Coyne AG;Abell C;Boshoff HIM;Wyatt PG;Rhee KY;Blundell TL;Barry CE 3rd;Mizrahi V
Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4′-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4′-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target.
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DOI：
10.1016/j.bbrc.2011.11.099
发表时间：
2012-01-13
影响因子：
3.1
作者：
Kaskow BJ;Proffitt JM;Blangero J;Moses EK;Abraham LJ
通讯作者：
Abraham LJ
影响因子：
5.3
作者：
Gopal P;Nartey W;Ragunathan P;Sarathy J;Kaya F;Yee M;Setzer C;Manimekalai MSS;Dartois V;Grüber G;Dick T
通讯作者：
Dick T
影响因子：
3.2
作者：
Balibar, Carl J.;Hollis-Symynkywicz, Micah F.;Tao, Jianshi
通讯作者：
Tao, Jianshi
影响因子：
3.7
作者：
Kumar A;Casey A;Odingo J;Kesicki EA;Abrahams G;Vieth M;Masquelin T;Mizrahi V;Hipskind PA;Sherman DR;Parish T
通讯作者：
Parish T
影响因子：
56.9
作者：
Andries, K;Verhasselt, P;Jarlier, V
通讯作者：
Jarlier, V