Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent

Rakesh Narang; Raj Kumar; Sourav Kalra; Surendra Kumar Nayak; Gopal L Khatik; Gadekula Naresh Kumar; Kalvatala Sudhakar; Sachin Kumar Singh

doi:10.1016/j.ejmech.2019.111644

Recent advancements in mechanistic studies and structure activity relationship of F_oF₁ ATP synthase inhibitor as antimicrobial agent

Eur J Med Chem. 2019 Nov 15:182:111644. doi: 10.1016/j.ejmech.2019.111644. Epub 2019 Aug 27.

Authors

Rakesh Narang¹, Raj Kumar², Sourav Kalra³, Surendra Kumar Nayak⁴, Gopal L Khatik⁴, Gadekula Naresh Kumar⁴, Kalvatala Sudhakar⁴, Sachin Kumar Singh⁴

Affiliations

¹ Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, 136119, India. Electronic address: rakeshnrng@gmail.com.
² Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151001, India. Electronic address: raj.khunger@gmail.com.
³ Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151001, India.
⁴ School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, India.

PMID: 31493745
DOI: 10.1016/j.ejmech.2019.111644

Abstract

The emergence of drug resistance in infectious microbial strains can be overcome by development of novel drug molecules against unexploited microbial target. The success of Bedaquiline in recent years, as F_oF₁ ATP synthase inhibitor against XDR and MDR mycobacterium strains, has resulted in further exploration to identify more potent and safe drug molecules against resistant strains. F_oF₁ ATP synthase is the main energy production enzyme in almost all eukaryotes and prokaryotes. Development of bacterial ATP synthase inhibitors is a safe approach, without causing harm to mammalian cells due to structural difference between bacterial and mammalian ATP synthase target sites. This review emphasizes on providing the structural insights for F_oF₁ ATP synthase of different prokaryotes and will help in the design of new potent antimicrobial agents with better efficacy. Further, applications of synthetic and natural active antimicrobial ATP synthase inhibitors, reported by different research groups are summarized. Their SAR and mode of actions are also analysed.

Keywords: Antimicrobial; Aurovertin; Bedaquiline; FoF1 ATP synthase inhibitor; Heterocyclic; Oligomycin; Peptides; Polyphenols; Sesquiterpenes; Steroidal alkaloids.

Publication types

Review

MeSH terms

Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium / drug effects*
Mycobacterium / enzymology
Proton-Translocating ATPases / antagonists & inhibitors*
Proton-Translocating ATPases / metabolism
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Proton-Translocating ATPases