Structure-based identification of potential natural compound inhibitors targeting bacterial cytoskeleton protein FtsZ from Acinetobacter baumannii by computational studies

Abstract

Acinetobacter baumannii is one of the multi-drug-resistant pathogens responsible for hospital-acquired infections reported worldwide. Clinically it is challenging to treat these pathogens as they have developed resistance against the existing class of antibiotics. Hence, there is an urgent need to develop a new class of antibiotics against these pathogens to prevent the spread of infections and mortality. In Acinetobacter baumannii, the filamentous temperature-sensitive mutant Z protein polymerizes at the imminent division site to form a Z-ring at the mid-point of the cell and act as a scaffold to recruit other cell division proteins involved in orchestrating septum synthesis in bacteria. Perturbation in the assembly of FtsZ affects bacterial cell dynamics and survival. Hence, FtsZ has emerged as a new drug target in antibiotic discovery to identify compounds that inhibit bacterial cell division. In this study, we have performed a virtual screening of 30,000 compounds from the ZINC Biogenic natural compound library targeting the nucleotide-binding site of FtsZ from Acinetobacter baumannii. We have identified 8 new natural compounds with binding energy in the range of −8.66 to −6.953 kcal/mol and analyzed them by 200 ns molecular dynamics simulations. Out of these eight compounds, ZINC14708526 showed the best binding with relatively optimal drug-likeness and medicinal chemistry as a potent inhibitor of abFtsZ. Thus, the identified FtsZ inhibitor ZINC14708526 is a promising lead compound to develop potent antimicrobial agents against Acinetobacter baumannii infections.

Communicated by Ramaswamy H. Sarma

Keywords:

• FtsZ
• cell division
• A. baumannii
• antimicrobial agent
• ZINC natural compound

Disclosure statement

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

Ethical approval

The article does not involve any study with human participants or animals performed by any of the authors.

CRediT authorship contribution statement

SRC: Methodology, Validation, Formal analysis, Writing, Review & editing, and Visualization. RS and TK: Methodology, Formal analysis, Investigation, Data curation. FN and SS: Formal analysis. MIK: data curation. MK and PK: Writing - Review & editing and Visualization. ASE: Methodology, Validation, Formal analysis, Investigation, Data curation, Writing - Review & editing and Visualization.

Additional information

Funding

This work was financially supported by grants from ICMR (ISRM/12/(123)/2020).