title: Avenaciolides: potential MurA-targeted inhibitors against peptidoglycan biosynthesis in methicillin-resistant Staphylococcus aureus (MRSA).
abstract: Discovery of new antibiotics for combating methicillin-resistant Staphylococcus aureus (MRSA) is of vital importance in the post-antibiotic era. Here, we report four avenaciolide derivatives (1-4) isolated from Neosartorya fischeri, three of which had significant antimicrobial activity against MRSA. The morphology of avenaciolide-treated cells was protoplast-like, which indicated that cell wall biosynthesis was interrupted. Comparing the structures and minimum inhibitory concentrations of 1-4, the α,β-unsaturated carbonyl group seems to be an indispensable moiety for antimicrobial activity. Based on a structural similarity survey of other inhibitors with the same moiety, we revealed that MurA was the drug target. This conclusion was validated by (31)P NMR spectroscopy and MS/MS analysis. Although fosfomycin, which is the only clinically used MurA-targeted antibiotic, is ineffective for treating bacteria harboring the catalytically important Cys-to-Asp mutation, avenaciolides 1 and 2 inhibited not only wild-type but also fosfomycin-resistant MurA in an unprecedented way. Molecular simulation revealed that 2 competitively perturbs the formation of the tetrahedral intermediate in MurA. Our findings demonstrated that 2 is a potent inhibitor of MRSA and fosfomycin-resistant MurA, laying the foundation for the development of new scaffolds for MurA-targeted antibiotics.
authors.affiliation: Institute of Biological Chemistry, §Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, #Genomics Research Center, and ▽Agricultural Biotechnology Research Center, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Ching-Ming
authors.initials: CM
authors.lastname: Chang
authors.forename: Jeffy
authors.initials: J
authors.lastname: Chern
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Chen
authors.forename: Kai-Fa
authors.initials: KF
authors.lastname: Huang
authors.forename: Chein-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Yang
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D055326:Neosartorya / Q000737:chemistry; D010457:Peptidoglycan / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007783:Lactones; D010457:Peptidoglycan; C100081:avenaciolide; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase