Chrysophaentins A-H, antibacterial bisdiarylbutene macrocycles that inhibit the bacterial cell division protein FtsZ.
Eight new antimicrobial natural products named chrysophaentins A-H belonging to a new structural class have been isolated from the marine chrysophyte alga Chrysophaeum taylori. Their structures were determined by extensive 2D NMR and MS techniques and are characterized by the presence of two polyhalogenated, polyoxygenated omega,omega'-diarylbutene units connected by two ether bonds to form the suite of macrocyclic natural products. Chrysophaentin A, the most potent of these antibiotics, inhibited the growth of clinically relevant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MIC(50) 1.5 +/- 0.7 microg/mL), multidrug-resistant S. aureus (1.3 +/- 0.4 microg/mL), and vancomycin-resistant Enterococcus faecium (MIC(50) 2.9 +/- 0.8 microg/mL). In vitro enzyme assays and transmission electron microscopy showed chrysophaentin A to inhibit the GTPase activity of the bacterial cytoskeletal protein FtsZ with an IC(50) value of 6.7 +/- 1.7 microg/mL, as well as GTP-induced formation of FtsZ protofilaments. Saturation Transfer Difference (STD) NMR experiments further confirmed chrysophaentin A binds to FtsZ, and NMR competition experiments with GTPgammaS showed chrysophaentin A and GTP to bind competitively to FtsZ. Last, molecular docking simulations provided a low energy model in which chrysophaentin A binds in and occludes a large portion of the GTP binding site of FtsZ in a manner that is consistent with the binding epitope determined by STD NMR.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0820, USA.
Alberto
A
Plaza
Jessica L
JL
Keffer
Giuseppe
G
Bifulco
John R
JR
Lloyd
Carole A
CA
Bewley
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D056890:Eukaryota / Q000737:chemistry; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D000432:Methanol / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D047028:Macrocyclic Compounds; D020558:GTP Phosphohydrolases; D000432:Methanol