Identifying Novel Inhibitors Against Klebsiella pneumoniae carbanepenamse-2 Enzymes Found in Carbapenem-Resistant Bacteria Through Structure-Based Small Molecule Virtual Screening

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2024-05-02

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Several nosocomial infections in the hospital setting are caused by Klebsiella pneumoniae, a gram-negative bacterium that causes diseases ranging from pneumonia to infected bodily lesions. K. pneumoniae has recently exhibited the production of a hydrolase enzyme identified as Klebsiella pneumoniae carbapenemase-2 (KPC-2), which confers resistance against “last line of defense” carbapenem antibiotics derived from the beta-lactam drug class. In these experiments, high-throughput ligand docking programs GOLD and ICM were employed to identify novel compounds for potential inhibition against KPC-2. Structure-based screening of small molecule libraries revealed that ligands ZINC23337780 and ZINC12003014 exhibited a strong binding affinity for KPC-2, indicating a potential for inhibition of enzymatic activity via conformational protein changes. Physiochemical changes associated with substrate binding were analyzed in wet-lab trials comprised of differential scanning fluorimetry (DSF) and chromogenic substrate (Nitrocefin) assays. This allowed for both a quantitative and qualitative analysis of inhibition against KPC-2 by comparing biochemical activity between the apoenzyme and the enzyme in complex with a screened novel inhibitor. By coupling physical assays with the aforementioned high-throughput screening techniques, the analysis of two small molecules against KPC-2 introduces the possibility for further development of these compounds into viable drug therapeutics that uphold the efficacy of carbapenem antibiotics used in clinical treatment plans.

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