title: Evaluation of inhibitory action of novel non β-lactam inhibitor against Klebsiella pneumoniae carbapenemase (KPC-2).
abstract: The use of three classical β-lactamase inhibitors (Clavulanic acid, tazobactam and sulbactam) in combination with β-lactam antibiotics is presently the mainstay of antibiotic therapy against Gram-negative bacterial infections. However these inhibitors are unable to inhibit carbapenemase KPC-2 effectively. They being β-lactam derivatives behave as substrates for this enzyme instead of inactivating it. We have initiated our study to check the in vitro inhibition activity of the two novel screened inhibitors (ZINC01807204 and ZINC02318494) in combination with carbapenems against KPC-2 expressing bacterial strain and their effect on purified enzyme KPC-2. The MIC values of meropenem and ertapenem showed maximum reduction (8 folds) in combination with screened compounds (ZINC01807204 and ZINC02318494). CLSM images also depicted their strong antibacterial activity in comparison to conventional β-lactamase inhibitors. Moreover no toxic effect has been shown on HeLa cell line. Though the IC50 value of ZINC01807204 was high (200 µM), it exhibited fairly good affinity for KPC-2 (Ki = 43.82 µM). With promising results this study identifies ZINC01807204 as a lead molecule for further optimization and development of more potent non β-lactam inhibitors against KPC-2.
authors.affiliation: Medical Microbiology and Molecular Biology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
authors.forename: Arbab
authors.initials: A
authors.lastname: Khan
authors.affiliation: Medical Microbiology and Molecular Biology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Faheem
authors.affiliation: Medical Microbiology and Molecular Biology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
authors.forename: Mohd
authors.initials: M
authors.lastname: Danishuddin
authors.affiliation: Medical Microbiology and Molecular Biology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
authors.forename: Asad U
authors.initials: AU
authors.lastname: Khan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D002460:Cell Line; D000077727:Ertapenem; D006367:HeLa Cells; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D013845:Thienamycins / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000187:drug effects*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases; C547585:beta-lactamase KPC-2, Klebsiella pneumoniae; D000077731:Meropenem; D000077727:Ertapenem