Discovery of bacterial fatty acid synthase inhibitors from a Phoma species as antimicrobial agents using a new antisense-based strategy.
Fatty acids are essential for bacterial growth and viability, with the type II fatty acid synthesis (FAS II) pathway being a potential antibacterial target. A new, selective, and highly sensitive whole cell-based antisense strategy has been designed to screen for natural product inhibitors of FabH/F of the FAS II pathway using a high-throughput two-plate agar-based differential sensitivity assay (FabF(2)p). An antisense assay along with the FASII enzyme prepared from Staphylococcus aureus was used for bioactivity-guided fractionation, leading to the isolation of phomallenic acids A-C (1-3) from a leaf litter fungus identified as Phoma sp. Compounds 1-3 exhibited minimum detection concentrations (MDC) of 0.63, 0.31, and 0.15 microg/mL in the FabF(2P) assay, IC(50) values of 22, 3.4, and 0.77 microg/mL in the FASII enzyme assay, and minimum inhibitory concentrations (MIC) of 250, 7.8, and 3.9 microg/mL, respectively, against wild-type S. aureus. Phomallenic acid C (3), the analogue with the longest chain, exhibited the best overall activity within the phomallenic acids obtained and was superior to cerulenin and thiolactomycin, the two most studied and commonly used FabF inhibitors.
Natural Products Chemistry and Medicinal Chemistry and Human and Animal Infectious Diseases, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, USA.
John G
JG
Ondeyka
Deborah L
DL
Zink
Katherine
K
Young
Ronald
R
Painter
Srinivas
S
Kodali
Andrew
A
Galgoci
Javier
J
Collado
Jose Ruben
JR
Tormo
Angela
A
Basilio
Francisca
F
Vicente
Jun
J
Wang
Sheo B
SB
Singh
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000466:Alkadienes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001203:Ascomycota / Q000737:chemistry*; D054889:Fatty Acid Synthase, Type II; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000096:biosynthesis; D005602:France; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology
D000466:Alkadienes; D000900:Anti-Bacterial Agents; D005227:Fatty Acids; D009097:Multienzyme Complexes; D013876:Thiophenes; C509899:phomallenic acid A; C509900:phomallenic acid B; C509901:phomallenic acid C; C035068:thiolactomycin; D000123:Acetyltransferases; D064429:Fatty Acid Synthases; D054889:Fatty Acid Synthase, Type II