In vitro and ex vivo activity of new derivatives of acetohydroxyacid synthase inhibitors against Mycobacterium tuberculosis and non-tuberculous mycobacteria.
Sulfometuron methyl (SM) is an inhibitor of acetohydroxyacid synthase (AHAS), the first common enzyme in the branched-chain amino acid biosynthetic pathway, and shows activity against Mycobacterium tuberculosis both in vitro and in vivo. To develop AHAS inhibitor derivatives with more potent activity, 100 sulfonylurea analogues were screened for antimycobacterial activity against M. tuberculosis and non-tuberculous mycobacteria (NTM), and then evaluated for intracellular activity using mouse macrophages. Three new compounds with antimycobacterial activity comparable with that of SM were identified. These compounds exhibit significant activity against intracellular M. tuberculosis (including the drug-resistant M. tuberculosis strains), and NTM Mycobacterium abscessus and Mycobacterium kansasii, respectively.
Sohn
Hosung
H
Department of Microbiology, College of Medicine, Chungnam National University, 6 Munhwa-Dong, Jung-Ku, Daejeon 301-747, South Korea.
Lee
Kil-Soo
KS
Ko
Young-Kwan
YK
Ryu
Jae-Wook
JW
Woo
Jae-Choon
JC
Koo
Dong-Wan
DW
Shin
Sung-Jae
SJ
Ahn
Se-Jin
SJ
Shin
A-Rum
AR
Song
Chang-Hwa
CH
Jo
Eun-Kyeong
EK
Park
Jeong-Kyu
JK
Kim
Hwa-Jung
HJ
D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D013453:Sulfonylurea Compounds; D000095:Acetolactate Synthase