Gageostatins A-C, antimicrobial linear lipopeptides from a marine Bacillus subtilis.
Concerning the requirements of effective drug candidates to combat against high rising multidrug resistant pathogens, we isolated three new linear lipopeptides, gageostatins A-C (1-3), consisting of hepta-peptides and new 3-β-hydroxy fatty acids from the fermentation broth of a marine-derived bacterium Bacillus subtilis. Their structures were elucidated by analyzing a combination of extensive 1D, 2D NMR spectroscopic data and high resolution ESIMS data. Fatty acids, namely 3-β-hydroxy-11-methyltridecanoic and 3-β-hydroxy-9,11-dimethyltridecanoic acids were characterized in lipopeptides 1 and 2, respectively, whereas an unsaturated fatty acid (E)-7,9-dimethylundec-2-enoic acid was assigned in 3. The 3R configuration of the stereocenter of 3-β-hydroxy fatty acids in 1 and 2 was established by Mosher's MTPA method. The absolute stereochemistry of amino acid residues in 1-3 was ascertained by acid hydrolysis followed by Marfey's derivatization studies. Gageostatins 1-3 exhibited good antifungal activities with MICs values of 4-32 µg/mL when tested against pathogenic fungi (R. solani, B. cinerea and C. acutatum) and moderate antibacterial activity against bacteria (B. subtilis, S. aeureus, S. typhi and P. aeruginosa) with MICs values of 8-64 µg/mL. Futhermore, gageostatins 1-3 displayed cytotoxicity against six human cancer cell lines with GI₅₀ values of 4.6-19.6 µg/mL. It is also noteworthy that mixed compounds 1+2 displayed better antifungal and cytotoxic activities than individuals.
Department of Marine Biotechnology, University of Science and Technology, 176 Gajung-dong, 217 Gajungro Yuseong-gu, Daejeon, 305-350, Korea. stareqfakir@gmail.com.
Fakir Shahidullah
FS
Tareq
Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan, 426-744, Korea. yimina82@kiost.ac.
Min Ah
MA
Lee
Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan, 426-744, Korea. hslee@kiost.ac.
Hyi-Seung
HS
Lee
Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan, 426-744, Korea. jslee@kiost.ac.
Jong-Seok
JS
Lee
Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan, 426-744, Korea. yjlee@kiost.ac.
Yeon-Ju
YJ
Lee
Department of Marine Biotechnology, University of Science and Technology, 176 Gajung-dong, 217 Gajungro Yuseong-gu, Daejeon, 305-350, Korea. shinhj@kiost.ac.
Hee Jae
HJ
Shin
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001412:Bacillus subtilis / Q000378:metabolism*; D001419:Bacteria / Q000187:drug effects; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000737:chemistry; D005285:Fermentation; D005658:Fungi / Q000187:drug effects; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D005227:Fatty Acids; D055666:Lipopeptides