Objectives: Bacterial strains that produce New Delhi metal-β-lactamase 1 (NDM-1) are a worldwide health threat. It remains a challenging task to find a potent NDM-1 inhibitor for clinical practice.
Methods: Molecular docking and virtual screening of an in-house fungal natural product database for NDM-1 inhibitors were performed. Based on the screening results, the affinity and inhibition ability of potential NDM-1 inhibitors were determined using purified NDM-1. The efficacy of compounds in combination with four β-lactam antibiotics (meropenem, imipenem, ceftriaxone and ampicillin) was evaluated. Morphological changes in Klebsiella pneumoniae ATCC BAA-2146 after treatment with the compounds were visualised by transmission electron microscopy.
Results: In silico screening led to the identification of four fungal products as potential NDM-1 inhibitors. Emerione A (1), a methylated polyketide with bicyclo[4.2.0]octene and 3,6-dioxabicyclo[3.1.0]hexane functionalities, has significant activity in cells (Kd = 11.8 ± 0.6 μM; IC50 = 12.1 ± 0.9 μM) and potentiates the activity of meropenem against two kinds of NDM-1-producing Enterobacteriaceae. To the best of our knowledge, emerione A (1) is the second fungal metabolite reported to exhibit NMD-1 inhibitory activity. According to the structural novelty of our database, we also found a new structural compound, asperfunolone A (2), with potential NMD-1 inhibitory activity.
Conclusion: Considering the low toxicity of emerione A (1), it may represent a potential lead compound for anti-NDM-1 drug development.
Keywords: Antimicrobial activity; Carbapenem-resistant Enterobacteriaceae; Emerione A; Fungal natural products; NDM-1; Structure elucidation.
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