Abstract
Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1–8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1–8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens.
Highlights
In this study, the antimicrobial effects of naphtho-γ-pyrones 1–8 against Methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing E. coli, K. pneumoniae, P. aeruginosa, and E. faecalis were investigated
The structures of compounds 1–8 were determined by 1H
Fonsecinones A and C (2 and 3) are both potent FabI inhibitors of fungal origin and exhibited promising antibacterial activities against the nosocomial infection pathogens MRSA, P. aeruginosa, E. faecalis, E. coli, and ESBL-producing E. coli, with MIC values in the micromolar range. These bioactive naphtho-γ-pyrones may be suitable as new antibiotics because of their potent antimicrobial properties and low toxicities[15,17]
Summary
A combination of in vitro antibacterial screening and molecular docking techniques were employed to identify several bioactive naphtho-γ-pyrones (2, 3, 6, and 7) as potent antibiotics against a panel of drug-resistant microbial pathogens These compounds exhibit FabI inhibition as one antibacterial mode of Figure 3. Fonsecinones A and C (2 and 3) are both potent FabI inhibitors of fungal origin and exhibited promising antibacterial activities against the nosocomial infection pathogens MRSA, P. aeruginosa, E. faecalis, E. coli, and ESBL-producing E. coli, with MIC values in the micromolar range. These bioactive naphtho-γ-pyrones may be suitable as new antibiotics because of their potent antimicrobial properties and low toxicities[15,17]. The active naphtho-γ-pyrones found in this study may provide novel chemical scaffolds for the discovery of antibacterial agents
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