Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme.
Analogues of the antibiotic thiolactomycin, with biphenyl-based 5-substituents, were found to have excellent in vitro inhibitory activity against the recombinant Mycobacterium tuberculosis beta-ketoacyl-ACP synthase mtFabH condensing enzyme. In particular, 5-(4'-benzyloxy-biphen-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one exhibited approximately a 4-fold increased potency against this key condensing enzyme involved in M. tuberculosis mycolic acid biosynthesis, compared to thiolactomycin.
Senior
Suzanne J
SJ
School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Illarionov
Petr A
PA
Gurcha
Sudagar S
SS
Campbell
Ian B
IB
Schaeffer
Merrill L
ML
Minnikin
David E
DE
Besra
Gurdyal S
GS
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D054889:Fatty Acid Synthase, Type II; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D009097:Multienzyme Complexes; D009171:Mycolic Acids; D011994:Recombinant Proteins; D013876:Thiophenes; C035068:thiolactomycin; D000123:Acetyltransferases; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D064429:Fatty Acid Synthases; D054889:Fatty Acid Synthase, Type II