Document Detail

Discovery of bacterial fatty acid synthase inhibitors from a Phoma species as antimicrobial agents using a new antisense-based strategy.
MedLine Citation:
PMID:  16562839     Owner:  NLM     Status:  MEDLINE    
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.
John G Ondeyka; Deborah L Zink; Katherine Young; Ronald Painter; Srinivas Kodali; Andrew Galgoci; Javier Collado; Jose Ruben Tormo; Angela Basilio; Francisca Vicente; Jun Wang; Sheo B Singh
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of natural products     Volume:  69     ISSN:  0163-3864     ISO Abbreviation:  J. Nat. Prod.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-27     Completed Date:  2006-05-08     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7906882     Medline TA:  J Nat Prod     Country:  United States    
Other Details:
Languages:  eng     Pagination:  377-80     Citation Subset:  IM    
Natural Products Chemistry and Medicinal Chemistry and Human and Animal Infectious Diseases, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, USA.
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MeSH Terms
Acetyltransferases / antagonists & inhibitors*
Alkadienes* / chemistry,  isolation & purification,  pharmacology
Anti-Bacterial Agents* / chemistry,  isolation & purification,  pharmacology
Ascomycota / chemistry*
Fatty Acid Synthetase Complex / antagonists & inhibitors*
Fatty Acid Synthetase Complex, Type II
Fatty Acids / biosynthesis
Methicillin Resistance
Microbial Sensitivity Tests
Molecular Structure
Multienzyme Complexes / antagonists & inhibitors*
Staphylococcus aureus / drug effects*
Thiophenes / pharmacology
Reg. No./Substance:
0/Alkadienes; 0/Anti-Bacterial Agents; 0/Fatty Acids; 0/Multienzyme Complexes; 0/Thiophenes; 0/phomallenic acid A; 0/phomallenic acid B; 0/phomallenic acid C; 82079-32-1/thiolactomycin; EC 2.3.1.-/Acetyltransferases; EC 6.-/Fatty Acid Synthetase Complex; EC 6.-/Fatty Acid Synthetase Complex, Type II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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