Treatment Strategy for a Multidrug-Resistant <i>Klebsiella</i> UTI

Fleming, Erin E.; Heil, Emily L.; Hynicka, Lauren M.

doi:10.1177/1060028013509974

Cited by 6 publications

(1 citation statement)

References 24 publications

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“…With the alarming increase in multiple drug resistance, treating infections by combination therapies have become an unstoppable trend. − In clinical, the treatments for severe MRSA or other multiple-drug-resistant pathogens require not only the originally used antibiotics but also the combination of fosfomycin to facilitate efficacy. ,, Because 2 shows the potency toward fosfomycin-resistant model ( Ec MurA C115D overexpressed in E. coli BL21), 2 could also be used not only in combination therapies but also in treating fosfomycin-resistant pathogens.…”

Section: Discussionmentioning

confidence: 99%

Avenaciolides: Potential MurA-Targeted Inhibitors Against Peptidoglycan Biosynthesis in Methicillin-Resistant Staphylococcus aureus (MRSA)

Chang¹,

Chern²,

Chen

et al. 2014

J. Am. Chem. Soc.

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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.

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