Bacterial and mammalian F1FO-ATPase: Structural similarities and divergences to exploit in the battle against Mycobacterium tuberculosis

Abstract

The inner mitochondrial membrane, thylakoid membrane of chloroplasts and bacterial plasma membrane play a central role in energy transduction processes exploiting a ubiquitous membrane-bound enzyme complex known as F₁F_O-ATPase. The enzyme maintains the same function of ATP production between the species and a basic molecular mechanism of enzymatic catalysis during ATP synthesis/hydrolysis. However, small structural divergences distinguish prokaryotic ATP synthases, embedded in cell membranes, from eukaryotic ones localized in the inner mitochondrial membrane designating the bacterial enzyme as drug targets. In antimicrobial drug design, the membrane-embedded c-ring of the enzyme becomes the key protein of candidate compounds, such as diarylquinolines in tuberculosis, that inhibit the mycobacteria F₁F_O-ATPase without affecting mammalian homologs. The drug known as bedaquiline can target uniquely the structure of the mycobacterial c-ring. This specific interaction could address at the molecular level the therapy of infections sustained by antibiotic-resistant microorganisms.

Keywords: ATP synthase; Bacteria; Bedaquiline; Binding site; Drugs; Mitochondria.