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Multiple antibiotic-resistant strains of  Klebsiella pneumoniae  can cause life-threatening infections. Bacterial enoyl-acyl carrier protein (ACP) reductases (ENRs) are considered critical targets for developing antibiotics. Our current study aims to identify inhibitors of  K. pneumoniae  ENRs (FabI and FabV). Due to the unavailability of experimental structures, protein models of FabI and FabV were predicted and validated in this study. Virtual screening of the 1930 FDA-approved drug database was conducted against the active site of the FabI protein with the help of the LEA3D server, and carfilzomib was chosen among the screened drugs for further docking studies. Carfilzomib, a proteasome inhibitor used in the treatment of multiple myeloma, was among the best-suited compounds obtained from the virtual screening and was found to be bactericidal in the  in vitro  experiment. Carfilzomib was docked against the active sites of the FabI and FabV proteins, and the ENR of  Mycobacterium tuberculosis , InhA. Carfilzomib showed a high binding affinity with all three proteins. Molecular dynamics (MD) simulations were conducted following the docking studies. MD simulations revealed that carfilzomib binds strongly to the active sites of the above mentioned ENRs. Our study found that carfilzomib is a potential inhibitor of the ENRs of  K. pneumoniae  and  M. tuberculosis.  This is a possible mechanism of its bactericidal property against  M. tuberculosis  observed  in vitro  in addition to its predicted actions on zinc-dependent metalloprotease-1 and peptide deformylase, two other drug target enzymes of  M. tuberculosis . Our study suggests that this drug could be used as a lead compound to develop antibiotics that can selectively act against ENRs of bacteria, without interfering with the activities of human proteasome. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Carfilzomib as a potential inhibitor of NADH-dependent enoyl-acyl carrier protein reductases of  Klebsiella pneumoniae  and  Mycobacterium tuberculosis  as a drug target enzyme: insights from molecular docking and molecular dynamics