Avenaciolides, secondary metabolites from indigenous fungus Neosartorya fischeri, on inhibiting methicillin-resistant Staphylococcus aureus (MRSA)
Date Issued
2015
Date
2015
Author(s)
張靖敏
Abstract
Antibiotics, the major breakthrough of modern medicine, play a pivotal role in many successful medical practices. However, the emergence of resistant traits against multiple classes of antibiotics has progressively narrowed the available treatment options for some pathogens for decades. Among the Gram-positive drug resistant microbes, methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for nosocomial and community-acquired bacterial infections around the world. Since we are now living in the post-antibiotics era in which the crisis of antimicrobial resistance is worse than ever before, discovering alternative antibiotics is urgent to counteract the ever increasing phenomenon. In this study, we report four avenaciolide derivatives (1-4) isolated from Neosartorya fischeri, an indigenous fungus from Hualien, Taiwan, three of which had significant antimicrobial activity against MRSA. Based on the TEM results, the morphology of avenaciolide-treated cells was protoplast-like, which indicated that cell wall biosynthesis was interrupted. Comparing the structures and MICs of 1-4, the the a,b-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 31P 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.
Subjects
MRSA
post-antibiotics age
avenaciolide derivatives
Neosartorya fischeri
MurA-targeted antibiotic
Type
thesis