In silico strategies for identifying therapeutic candidates against Acinetobacter baumannii: spotlight on the UDP-N-acetylmuramoyl-L-alanine-D-glutamate:meso-diaminopimelate ligase (MurE)

Abstract

The opportunistic bacterium Acinetobacter baumannii, which belongs to ESKAPE group of pathogenic bacteria, is leading cause of infections associated with gram-negative bacteria. Acinetobacter baumannii causes severe diseases, such as VAP (ventilator-associated pneumonia), meningitis, and UTI (urinary tract infections) among the nosocomial infections contracted in hospitals. The high infection rate and growing resistance to the vast array of antibiotics makes it paramount to look for new therapeutic strategies against this pathogen. The most promising therapeutic targets are the proteins involved in the synthesis of peptidoglycan which is chief component of bacterial cell wall, MurE is one of those enzymes and is responsible for the addition of one unit of meso-diaminopimelic acid (meso-A2pm) to the nucleotide precursor, UDPMurNAc-L-Ala-D-Glu, and aids in the formation of crosslinker pentapeptide chain. The three-dimensional structure of MurE was modelled using homology modelling technique and then vHTS was performed using this model against Approved Drug Library on DrugRep server using AutoDock Vina. Out of 500 drug molecules, two were selected based on estimated binding affinity, interaction pattern, interacting residues, etc. The selected drug molecules are DB12887 (Tazemetostat) and DB13879 (Glecaprevir). Then, MD simulations were performed on native MurE and its complexes with ligands to examine their dynamical behaviour, stability, integrity, compactness, and folding properties. The protein-ligand complexes were then subjected to binding free energy calculations using the MM/PBSA-based binding free energy analysis and the values are −109.788 ± 8.03 and −152.753 ± 11.98 kcal for MurE-DB12887 and MurE-DB13879 complex, respectively. All the analysis performed on MD trajectories for the complexes of these ligands with protein provided plenty of dependable evidences to consider these molecules for inhibition of MurE enzyme from A. baumannii.

Communicated by Ramaswamy H. Sarma

Keywords:

• ESKAPE
• MD simulations
• MM/PBSA
• peptidoglycan
• virtual screening
• MurE

Acknowledgements

Dr. Amit Kumar Singh thanks the Indian Council of Medical Research (ICMR) and Indian National Science Academy (INSA), New Delhi, India. The authors thank Sharda University, Greater Noida, India for support.

Author contributions

Ankit Kumar: data curation, formal analysis, methodology, software, visualization, writing—original draft, writing—review and editing. Pratyaksha Singh: data collection. Ekampreet Singh: writing—review and editing. Monika Jain: formal analysis, writing—review and editing. Jayaraman Muthukumaran: validation, writing—review and editing. Amit Kumar Singh: conceptualization, investigation, supervision, validation, writing—review and editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

Not applicable.

Data availability statement

Data and materials are available on request from the authors.

Additional information

Funding

None.