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

Abstract

Klebsiella pneumoniae (K. pneumoniae) 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 K. pneumoniae infections. Prolonged exposure to β-lactam antibiotics leads to the development of resistance. The major reason for the β-lactam resistance in K. pneumoniae is the secretion of the enzyme K. pneumoniae carbapenemase (KPC). Secretion of KPC-2 and its variant KPC-3 by the K. pneumoniae 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 c-score value of 4.03 with greater stability than the KPC-2–imipenem c-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 K. pneumoniae.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

HIGHLIGHTS

• 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.

Keywords:

• Carbapenemase
• resistance
• inhibitor
• analogues
• interaction
• stability

Acknowledgment

The authors would like to thank the management of VIT for providing the necessary facilities to carry out this research project.

Disclosure statement

The authors declare that there is no conflict of interest.

Figure 7. RMSD plot. KPC-3–tazobactam (black), KPC-3–ZINC48682523 (magenta), KPC-3–ZINC50209041 (green) and KPC-3–ZINC50420049 (blue) complexes.

Figure 8. H-bond interactions. KPC-3–tazobactam complex (black), KPC-3–ZINC48682523 complex (magenta), KPC-3–ZINC50209041 complex (green) and KPC-3–ZINC50420049 complex (blue).

Additional information

Funding

SR and AA gratefully acknowledge the funding from DST-SERB [Project File no. EMR/2016/001849] for the present study.