Lab Group 2019: From left back: Yi Boa Ang, Liam Harold, Cara Adolph, Zoe Williams. Front Left: Kiel Hards, Sam Purchas.
Bacteria live in all environments on earth, ranging from our guts to clouds, volcanoes and everywhere in-between. A near universal truth for these diverse ecosystems is that bacteria live in complex microbial communities, interacting and communicating with other microbes in a variety of poorly understood ways. Many bacteria generate energy for growth by a process called cellular respiration. Some bacteria cannot perform respiration on their own, only doing so with the help of another bacterium. These bacteria often partake in a process called interspecies electron transfer, where different steps in respiration are connected between two or more bacteria to form a complete circuit.
Several infectious bacteria exist that contain incomplete respiration pathways and it has historically been assumed that they don’t generate energy by respiration. However, the virulence of these bacteria depends on the presence of these partial respiration steps. This suggests that genes from other bacteria may be essential for opportunistic pathogens in vivo and hence make valuable drug targets.
My work focuses on understanding the unusual ways that bacteria generate energy, in isolation or in communities, and developing antibiotics that target bacterial energy generation. This field of research is broadly known as “bioenergetics” and our previous work has helped develop several new antibiotics for treatment of Tuberculosis.
My aim is to extend the reach of bioenergetic-targeting drugs to a broad range of health problems, through increased understanding of the bioenergetic systems of pathogenic bacteria. I address these questions through a diverse range of techniques including:
Clinical: A paradigm shift for antimicrobial drug development. Antimicrobial development typically focuses on essential genes in the target pathogen. However, this work will identify a new paradigm shift: genes from other bacteria may be essential for opportunistic pathogens in vivo and hence make valuable drug targets.
Fundamental: Rewriting the textbook on microbial metabolism. Fundamental understanding of microbial respiration comes from single-culture studies in bacteria that encode intact respiratory chains. This work will show how energy generation in microbial communities is vastly different to single culture at a molecular level.
Biotechnological: Enhancing the microbial production of electricity. Electrically active bacteria, such as species of Geobacter, are subject to intense research for their ability to generate electricity in a technology called a microbial fuel cell. Finding novel mechanisms of interspecies electron transfer in previously unrecognized bacteria widens the scope of this technology.
These projects address a wide-range of pathogenic bacteria, with specific foci on Group B Streptococcus, Mycobacterium tuberculosis and Staphylococcus aureus.
Opportunities for PhD projects are available. There are a diverse range of projects available under the overarching projects listed above. They encompass a wide range of pathogenic bacteria in either mono- or poly-culture models.
Opportunities for MSc/BSc(Hons)/PGDipSci projects are also available. Please contact Dr. Kiel Hards for further details.
2019-Present. 5 lecture module on bacterial metabolism and persistence.
2017-2018. 4 lecture module on “Hierarchical control of electron acceptor utilization in E. coli”.
Categorized by year of award.
Up to date information can be found at: https://scholar.google.co.nz/citations?user=JiM-K0cAAAAJ&hl=en
Lee BS, Hards K, Engelhart CA, Hasenoehrl EJ, Kalia NP, Mackenzie JS, Sviriaeva E, Chong SMS, Manimekalai MSS, Koh VH, Chan J, Xu J, Alonso S, Miller MJ, Steyn AJC, Gruber G, Schnappinger D, Berney M, Cook GM, Moraski GC, Pethe K (2020). Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis. EMBO Mol Med. In press
McKinlay JB, Cook GM, Hards K (2020). Microbial energy management - A product of three broad tradeoffs. Adv Microb Physiol. 77:139-185
Nizi MG, Desantis J, Nakatani Y, Massari S, Mazzarella MA, Shetye G, Sabatini S, Barreca ML, Manfroni G, Felicetti T, Ruston-Green R, Hards K, Latacz G, Satala G, Bojarski AJ, Cecchetti V, Kolar MH, Handzlik J, Cook GM, Franzblau SG, Tabarrini O (2020). Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors. Eur J Med Chem. 201, 112420
Harbison-Price N, Ferguson SA, Heikal A, Taiaroa G, Hards K, Nakatani Y, Rennison D, Brimble MA, El-Deeb IM, Bohlmann L, McDevitt CA, Itzstein M, Walker MJ, Cook GM. 2020, Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2. mSphere. 5(2)
Lee BM, Almeida D V, Afriat-Jurnou L, Aung HL, Forde BM, Hards K, Pidot SJ, Ahmed FH, Mohamed AE, Taylor MC. 2020, Predicting nitroimidazole antibiotic resistance mutations in Mycobacterium tuberculosis with protein engineering. PLoS Pathog. 16(2):e1008287
Jeuken LJC, Hards K, Nakatani Y. 2020, Extracellular Electron Transfer: Respiratory or nutrient homeostasis? J Bacteriol. 202(7)
Saw WG, Wu ML, Ragunathan P, Biuković G, Lau AM, Harikishore A, Cheung CY, Hards K, Sarathy JP, Bates RW, Cook GM, Dick T, Grüber G. 2019, Disrupting coupling within mycobacterial F-ATP synthases subunit ε casuses dysregulated energy production and cell wall biosynthesis. Sci. Rep. 9:1-15
Cordero PRF, Grinter R, Hards K, Cryle MJ, Warr CG, Cook GM, Greening C. 2019, Two uptake hydrogenases differentially interact with the aerobic respiratory chain during mycobacterial growth and persistence. J. Biol. Chem. 294(50):18980-18991
Hards K, Adolph C, Harold LK, McNeil MB, Cheung C, Jinich A, Rhee K, Cook GM. 2019, Two for the price of one: attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents. Prog Biophys Mol Biol. 152:35-44
Hards K, Rodriguez SM, Cairns C, Cook GM. 2019, Alternate quinone coupling in a new class of succinate dehydrogenase may potentiate mycobacterial respiratory control. FEBS Lett. 593:475-486
Santoso KT, Cheung C-Y, Hards K, Cook GM, Stocker BL, Timmer MSM. 2019, Synthesis and Investigation of Phthalazinones as Antitubercular Agents. Chem Asian J 14(8):1278–1285.
Harold LK, Antoney J, Ahmed FH, Hards K, Carr PD, Rapson T, Greening C, Jackson CJ, Cook GM. 2019. FAD-sequestering proteins protect mycobacteria against hypoxic and oxidative stress. J. Biol. Chem. 294(8):2903-2912
Lu X, Williams Z, Hards K, Tang J, Cheung C, Aung HL, Wang B, Liu Z, Hu X, Lenaerts A, Woolhiser L, Hastings C, Zhang X, Wang Z, Rhee K, Ding K, Zhang T, Cook GM. 2018. Pyrazolo[1,5-a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis. ACS Infect. Dis., 5:239-249
Hards K, McMillan DGG, Schurig-Briccio LA, Gennis RB, Lill H, Bald D, Cook GM. 2018. Ionophoric effects of the antitubercular drug bedaquiline. Proc Natl Acad Sci U S A.115:7326-7331
Hards K, Cook GM. 2018. Targeting bacterial energetics to produce new antimicrobials. Drug Resist Updat. 36:1-12
Carere CR, Hards K, Houghton KM, Power JF, McDonald B, Collet C, Gapes DJ, Sparling R, Boyd ES, Cook GM, Greening C, Stott MB. 2017. Mixotrophy drives niche expansion of verrucomicrobial methanotrophs. ISME J., 11:2599-2910
Kalia NP, Hasenoehrl EJ, Ab Rahman NB, Koh VH, Ang MLT, Sajorda DR, Hards K, Grüber G, Alonso S, Cook GM, Berney M, Pethe K. 2017. Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. Proc Natl Acad Sci U S A., 114:7426-7431
Cook GM, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick DC, Fontes FL, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative phosphorylation as a target space for tuberculosis: success, caution, and future directions. In Tuberculosis and the Tubercle Bacilli (ed. Jacobs Jr WR, McShane H, Mizhari V, Orme IM), ASM Press, Washington DC
Heikal A, Hards K, Cheung C, Menorca A, Timmer MSM, Stocker BL, Cook GM. 2016. Activation of type II NADH dehydrogenase by quinolinequinones mediates antitubercular cell death. J. Antimicrob. Chemother., 71:2840–7.
Hards K, Cook GM. 2016. Compartmentalization of succinate dehydrogenase function in the diverse lifestyle conditions of an actinobacterium. Biochim. et Biophys.Acta – Bioenergetics, 1857:e86-e87
Medini K, Harris PWR, Menorca A, Hards K, Cook GM, Brimble MA. 2015. Synthesis and activity of a diselenide bond mimetic of the antimicrobial protein caenopore-5. Chem. Sci., 7(3):2005-2010
Greening C, Carere CR, Rushton-Green R, Harold LK, Hards K, Taylor MC, Morales SE, Stott MB, Cook GM. 2015. Persistence of dominant soil phylum Acidobacteria by trace gas scavenging. Proc. Natl. Acad. Sci. U. S. A., 112:10497-502
Hards K*, Robson JR*, Berney M, Shaw L, Bald D, Koul A, Andries K, Cook GM. 2015. Bactericidal mode of action of bedaquiline. J. Antimicrob. Chemother., 70:2028-2037
Greening C, Constant P, Hards K, Morales SE, Oakeshott JG, Russell RJ, Taylor MC, Berney M, Conrad R, Cook GM. 2015. Atmospheric hydrogen scavenging: from enzymes to ecosystems. Appl. Environ. Microbiol., 81:1190–1199.
Medini K, Harris PWR, Hards K, Dingley AJ, Cook GM, Brimble MA. 2015. Chemical Synthesis of A Pore-Forming Antimicrobial Protein, Caenopore-5, by Using Native Chemical Ligation at a Glu-Cys Site. ChemBioChem, 16:328–336.
Pecsi I*, Hards K*, Ekanayaka N, Berney M, Hartman T, Jacobs WR, Cook GM. 2014. Essentiality of Succinate Dehydrogenase in Mycobacterium smegmatis and Its Role in the Generation of the Membrane Potential Under Hypoxia. mBio, 5(4) .
Greening C, Berney M, Hards K, Cook GM, Conrad R. 2014. A soil actinobacterium scavenges atmospheric H2 using two membrane-associated, oxygen-dependent [NiFe] hydrogenases. Proc. Natl. Acad. Sci. U. S. A., 111:4257–4261.
McNeil MB, Hampton HG, Hards KJ, Watson BNJ, Cook GM, Fineran PC. 2014. The succinate dehydrogenase assembly factor, SdhE, is required for the flavinylation and activation of fumarate reductase in bacteria. FEBS Lett., 588:414–421.
Berney M, Greening C, Hards K, Collins D, Cook GM. 2014. Three different [NiFe] hydrogenases confer metabolic flexibility in the obligate aerobe Mycobacterium smegmatis. Environ. Microbiol., 16:318–330.
Cook GM, Greening C, Hards K, Berney M. 2014. Chapter One-Energetics of Pathogenic Bacteria and Opportunities for Drug Development. Adv. Microb. Physiol. 65:1–62.
Cook GM, Hards K, Vilchèze C, Hartman T, Berney M. 2014. Energetics of respiration and oxidative phosphorylation in mycobacteria. In Molecular Genetics of Mycobacteria (ed. Hatful GF, Jacobs Jr WR), ASM Press, Washington DC
*These authors contributed equally