A collaborative team led by Nikos Hatzakis, from the Nanoscience Center and Department of Chemistry University of Copenhagen (Denmark), and Lars Jeuken from University of Leeds (UK), have reported on a new and potentially promising drug target in antibiotic drug discovery.
Dubbed by the team as bacteria’s “Achilles heel”, the target constitutes the mechanism responsible for regulating Heme-copper oxidase (HCO). This enzyme exists in prokaryotes and eukaryotes and plays a key role in energy production during aerobic respiration; acting as a proton pump, it maintains a pH gradient (ΔpH), which generates a proton motive force (PMF) that in turn drives ATP synthesis.
By conducting a single-enzyme study, the team revealed that cytochrome bo3 from Escherichia coli, an HCO closely homologous to Complex IV in human mitochondria, can enter a rare, long-lifetime leak state during which proton flow is reversed. The probability of HCO entering the leak state was found to increase at higher ΔpH. By rapidly dissipating the PMF, the team inferred that the leak state may enable cytochrome bo3, and possibly other HCOs, to maintain a suitable ΔpH under extreme redox conditions.
Hatzakis explains: “I believe the leaking mechanism acts as a safety valve in the bacteria. If we can design a drug which targets such a safety valve in proton pumps, it would be a very powerful antibiotic indeed, so the leak state is a serious weakness.”
Li M, Jørgensen SK, McMillan DG et al. Single Enzyme Experiments Reveal a Long-Lifetime Proton Leak State in a Heme-Copper Oxidase. J. Am. Chem. Soc. 137 (51), 16055–16063 (2015).
Bacteria’s Achilles heel uncovered by single molecule chemistry: http://www.science.ku.dk/english/press/news/2016/b...