title: Energetics of pathogenic bacteria and opportunities for drug development.
abstract: The emergence and spread of drug-resistant pathogens and our inability to develop new antimicrobials to overcome resistance has inspired scientists to consider new targets for drug development. Cellular bioenergetics is an area showing promise for the development of new antimicrobials, particularly in the discovery of new anti-tuberculosis drugs where several new compounds have entered clinical trials. In this review, we have examined the bioenergetics of various bacterial pathogens, highlighting the versatility of electron donor and acceptor utilisation and the modularity of electron transport chain components in bacteria. In addition to re-examining classical concepts, we explore new literature that reveals the intricacies of pathogen energetics, for example, how Salmonella enterica and Campylobacter jejuni exploit host and microbiota to derive powerful electron donors and sinks; the strategies Mycobacterium tuberculosis and Pseudomonas aeruginosa use to persist in lung tissues; and the importance of sodium energetics and electron bifurcation in the chemiosmotic anaerobe Fusobacterium nucleatum. A combination of physiological, biochemical, and pharmacological data suggests that, in addition to the clinically-approved target F1Fo-ATP synthase, NADH dehydrogenase type II, succinate dehydrogenase, hydrogenase, cytochrome bd oxidase, and menaquinone biosynthesis pathways are particularly promising next-generation drug targets. The realisation of cellular energetics as a rich target space for the development of new antimicrobials will be dependent upon gaining increased understanding of the energetic processes utilised by pathogens in host environments and the ability to design bacterial-specific inhibitors of these processes.
authors.affiliation: Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. Electronic address: gregory.cook@otago.ac.nz.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cook
authors.affiliation: Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Chris
authors.initials: C
authors.lastname: Greening
authors.affiliation: Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Kiel
authors.initials: K
authors.lastname: Hards
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Berney
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D010088:Oxidoreductases / Q000378:metabolism; D018892:Proton-Motive Force
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases
keywords: Bacterial energetics; Drug targets; Pathogenic bacteria; Physiology; Respiration