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Abstract
The emergence of NDM-1 containing multi-antibiotic resistant "Superbugs" necessitates the needs of developing of novel NDM-1inhibitors. In this study, we report the discovery of novel NDM-1 inhibitors by multi-step virtual screening. From a 2,800,000 virtual drug-like compound library selected from the ZINC database, we generated a focused NDM-1 inhibitor library containing 298 compounds of which 44 chemical compounds were purchased and evaluated experimentally for their ability to inhibit NDM-1 in vitro. Three novel NDM-1 inhibitors with micromolar IC50 values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC50 of 29.6 ± 1.3 μM. Molecular dynamic simulation revealed that VNI-41 interacted extensively with the active site. In particular, the sulfonamide group of VNI-41 interacts directly with the metal ion Zn1 that is critical for the catalysis. These results demonstrate the feasibility of applying virtual screening methodologies in identifying novel inhibitors for NDM-1, a metallo-β-lactamase with a malleable active site and provide a mechanism base for rational design of NDM-1 inhibitors using sulfonamide as a functional scaffold.
Highlights
Antibiotics being used to treat or prevent infectious disease have revolutionized the practice of medicine
According to the U.S Centers for Disease Control and Prevention, more than two million people are affected by infectious diseases with antibiotic resistance and at least 23,000 people died each year in the United States [5]
While NDM-1 structures complexed with hydrolyzed antibiotics share a greater metal-ion separation (4.53 ± 0.11Å, 3Q6X 4.59 Å) with a slight outward flexing of His120 and His122, the binuclear Zn distance appears to be significantly less (3.72 ± 0.17Å, p < 0.001) in most apoNDM-1 structures (Table A in S1 File)
Summary
Antibiotics being used to treat or prevent infectious disease have revolutionized the practice of medicine. Without them numerous modern therapies such as organ transplantation and cancer chemotherapy would not be possible [1]. Overuse and/or misuse of antibiotics in farming and clinical practices has resulted in rising multidrug-resistance bacterial strains, among which gram-negative bacteria producing β-lactamases become the most prevalent [2,3,4]. According to the U.S Centers for Disease Control and Prevention, more than two million people are affected by infectious diseases with antibiotic resistance and at least 23,000 people died each year in the United States [5].
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