Identification of potential inhibitors for <i>Klebsiella pneumoniae</i> carbapenemase-3: a molecular docking and dynamics study

<i>Klebsiella pneumoniae</i> (<i>K. pneumoniae)</i> is a Gram-negative bacterium, which is a leading causal agent for nosocomial infections. Penicillin, cephalosporin and carbapenems along with the inhibitors such as tazobactam, sulbactam and clavulanic acid are prescribed for the treatment of <i>K. pneumoniae</i> infections. Prolonged exposure to β-lactam antibiotics leads to the development of resistance. The major reason for the β-lactam resistance in <i>K. pneumoniae</i> is the secretion of the enzyme <i>K. pneumoniae</i> carbapenemase (KPC). Secretion of KPC-2 and its variant KPC-3 by the <i>K. pneumoniae</i> strains causes resistance to both the substrate imipenem and the β-lactamase inhibitors. Hence, molecular docking and dynamics studies were carried out to analyze the resistance mechanism of KPC-2–imipenem and KPC-3–imipenem at the structural level. It reveals that KPC-3-imipenem has the highest <i>c</i>-score value of 4.03 with greater stability than the KPC-2–imipenem <i>c</i>-score value of 2.36. Greater the interaction between the substrate and the β-lactamase enzyme, higher the chances of hydrolysis of the substrate. Presently available β-lactamase inhibitors are also ineffective against KPC-3-expressing strains. This situation necessitates the need for development of novel and effective inhibitors for KPC-3. We have carried out the virtual screening process to identify more effective inhibitors for KPC-3, and this has resulted in ZINC48682523, ZINC50209041 and ZINC50420049 as the best binding energy compounds, having greater binding affinity and stability than KPC-3–tazobactam interactions. Our study provides a clear understanding of the mechanism of drug resistance and provides valuable inputs for the development of inhibitors against KPC-3 expressing <i>K. pneumoniae.</i> Communicated by Ramaswamy H. Sarma <b>HIGHLIGHTS</b>Molecular docking results in high binding energy between imipenem and KPC-3.Molecular dynamics results in higher stability of KPC-3-imipenem complex.Virtual screening was carried out to find novel inhibitors for KPC-3.Molecular dynamics reveals higher stability of novel inhibitors than tazobactam. Molecular docking results in high binding energy between imipenem and KPC-3. Molecular dynamics results in higher stability of KPC-3-imipenem complex. Virtual screening was carried out to find novel inhibitors for KPC-3. Molecular dynamics reveals higher stability of novel inhibitors than tazobactam.