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Discovery of novel new Delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening.

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.

SUBMITTER: Wang X

PROVIDER: S-EPMC4348537 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Discovery of novel new Delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening.

Wang Xuequan X Lu Meiling M Shi Yang Y Ou Yu Y Cheng Xiaodong X

PloS one 20150303 3

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 ...[more]

PMID: 25734558

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Project description:BackgroundCarbapenemase-producing Enterobacterales pose a serious clinical threat, particularly in high-burden settings of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae (CREK), where rapid detection tools are essential to aid patient management. In this study, we focused on blaNDM, the most frequently reported carbapenemase in the region, and evaluated a combined phenotypic (lateral flow) and genotypic (PCR and WGS) approach for its detection. This research underscores the utility of lateral flow assays as a practical alternative to resource-intensive genotypic methods, offering a scalable solution for settings with limited laboratory capacity.MethodOne hundred seventy-seven extensively drug-resistant strains were characterized using MALDI-TOF. Isolates were analyzed to detect Carbapenem-resistant Escherichia coli and Klebsiella pneumoniae (CREK) using disk diffusion, MIC test, and PCR targeting blaNDM. Antibiotic susceptibility patterns were analyzed and visualized using single-linkage hierarchical clustering, with results displayed on a permuted heat map. Immunochromatographic assay, RESIST-5 O.K.N.V.I (Coris Bioconcept®) was used for CREK isolates [(n = 17), positive and negative)] and Oxford Nanopore Sequencing was conducted on subsets [(n = 5) blaNDM-positive co-producers of blaNDM and blaOXA, and (n = 2) blaNDM-negative blaOXA producers) to evaluate the reliability of phenotypic and genotypic tests.ResultMost of the XDR strains (90%) were CREK, with K. pneumoniae (71.2%) more prevalent than E. coli (28.7%) (p < 0.05). All CREK strains exhibited complete resistance (100%) to multiple antibiotics with 66% showing sensitivity to levofloxacin. Furthermore, K. pneumoniae (57.8%) had higher blaNDM gene prevalence than E. coli (36.9%). Among blaNDM-positive CREK, lateral flow assay revealed approximately half of each bacteria type co-produced blaOXA (E.coli, 52.9%), and (K. pneumoniae, 47%). For blaNDM-negative strains, blaOXA was more prevalent in K. pneumoniae (82.35%) than E. coli (41%) (p < 0.05). Comparing phenotypic to genotypic assays, E. coli showed 100% (CI 80.49 - 100%) sensitivity and specificity with a high Kappa agreement coefficient (0.91) (CI 95% 0.661-1, p < 0.01), whereas K. pneumoniae assays had lower sensitivity and specificity (40%) (CI 5.27 - 85.34%), with a lower Kappa agreement coefficient (0.20) (CI 95% 0.104-0.298, p < 0.01).ConclusionThis study demonstrates the value of the RESIST-5 O.K.N.V.I. lateral flow assay as a rapid and reliable diagnostic tool for detecting blaNDM in Escherichia coli, with strong agreement to PCR and WGS. While performance for Klebsiella pneumoniae was lower, the assay offers a practical alternative in resource-limited settings, aiding antimicrobial stewardship and improving diagnostic capacities in high-burden regions.

Dataset Information

Discovery of novel new Delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening.

Publications

Discovery of novel new Delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening.

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