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.
Highlights
Klebsiella pneumoniae carbapenemase (KPC) is a molecular class A serine b-lactamase belonging to functional group 2f [1]
The activity of b-lactam antibiotics and b-lactamase inhibitors in combination have been successful in treatment of various infections caused by resistant bacteria but the KPC-2 b-lactamase have evolved to hydrolyze b-lactam inhibitors as substrates [9]
The cells were found to be resistant to all carbapenems used with Minimum inhibitory concentration (MIC) of 64 mg/ml, 64 mg/ml and 128 mg/ml for imipenem, meropenem and ertapenem respectively
Summary
Klebsiella pneumoniae carbapenemase (KPC) is a molecular class A serine b-lactamase belonging to functional group 2f [1]. KPC have drawn the attention of microbiologists worldwide because of its unique structural characteristics It has an overall structure like class A serine blactamases but share very little sequence similarity with other class A b-lactamases like CTX-M-1, TEM-1 and SHV-1 [5]. It possesses a large and shallow active site which can accommodate bulkier b-lactams making KPC-2 being dubbed as a ‘‘versatile b-lacatamse’’ [6,7]. The activity of b-lactam antibiotics and b-lactamase inhibitors in combination have been successful in treatment of various infections caused by resistant bacteria but the KPC-2 b-lactamase have evolved to hydrolyze b-lactam inhibitors as substrates [9]. We studied the toxicity effect of these compounds and further propose these novel inhibitors as potential scaffolds for further optimization against KPC-2
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