A picomolar transition state analogue inhibitor of MTAN as a specific antibiotic for Helicobacter pylori.
Campylobacter and Helicobacter species express a 6-amino-6-deoxyfutalosine N-ribosylhydrolase (HpMTAN) proposed to function in menaquinone synthesis. BuT-DADMe-ImmA is a 36 pM transition state analogue of HpMTAN, and the crystal structure of the enzyme-inhibitor complex reveals the mechanism of inhibition. BuT-DADMe-ImmA has a MIC(90) value of <8 ng/mL for Helicobacter pylori growth but does not cause growth arrest in other common clinical pathogens, thus demonstrating potential as an H. pylori-specific antibiotic.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Shanzhi
S
Wang
Antti M
AM
Haapalainen
Funing
F
Yan
Quan
Q
Du
Peter C
PC
Tyler
Gary B
GB
Evans
Agnes
A
Rinaldo-Matthis
Rosemary L
RL
Brown
Gillian E
GE
Norris
Steven C
SC
Almo
Vern L
VL
Schramm
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016481:Helicobacter Infections / Q000188:drug therapy; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*
C517547:4'-deaza-1'-aza-2'-deoxy-1'-(9-methylene)-immucillin A; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D009699:N-Glycosyl Hydrolases; D000225:Adenine