ORCID Profile
0000-0002-4833-0573
Current Organisation
Lorestan University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 25-11-2014
Abstract: M ycobacterium smegmatis is an obligate aerobe that harbours three predicted [ NiFe ] hydrogenases, Hyd 1 ( MSMEG _2262–2263), Hyd 2 ( MSMEG _2720‐2719) and Hyd 3 ( MSMEG _3931‐3928). We show here that these three enzymes differ in their phylogeny, regulation and catalytic activity. Phylogenetic analysis revealed that Hyd 1 groups with hydrogenases that oxidize H 2 produced by metabolic processes, and Hyd 2 is homologous to a novel group of putative high‐affinity hydrogenases. Hyd 1 and Hyd 2 respond to carbon and oxygen limitation, and, in the case of Hyd 1, hydrogen supplementation. Hydrogen consumption measurements confirmed that both enzymes can oxidize hydrogen. In contrast, the phylogenetic analysis and activity measurements of Hyd 3 are consistent with the enzyme evolving hydrogen. Hyd 3 is controlled by DosR , a regulator that responds to hypoxic conditions. The strict dependence of hydrogen oxidation of Hyd 1 and Hyd 2 on oxygen suggests that the enzymes are oxygen tolerant and linked to the respiratory chain. This unique combination of hydrogenases allows M . smegmatis to oxidize hydrogen at high ( Hyd 1) and potentially tropospheric ( Hyd 2) concentrations, as well as recycle reduced equivalents by evolving hydrogen ( Hyd 3). The distribution of these hydrogenases throughout numerous soil and marine species of actinomycetes suggests that oxic hydrogen metabolism provides metabolic flexibility in environments with changing nutrient fluxes.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2022
DOI: 10.1038/S42003-022-03110-8
Abstract: Increasing antimicrobial resistance compels the search for next-generation inhibitors with differing or multiple molecular targets. In this regard, energy conservation in Mycobacterium tuberculosis has been clinically validated as a promising new drug target for combatting drug-resistant strains of M. tuberculosis . Here, we show that HM2-16F, a 6-substituted derivative of the FDA-approved drug amiloride, is an anti-tubercular inhibitor with bactericidal properties comparable to the FDA-approved drug bedaquiline (BDQ Sirturo ® ) and inhibits the growth of bedaquiline-resistant mutants. We show that HM2-16F weakly inhibits the F 1 F o -ATP synthase, depletes ATP, and affects the entry of acetyl-CoA into the Krebs cycle. HM2-16F synergizes with the cytochrome bcc-aa 3 oxidase inhibitor Q203 (Telacebec) and co-administration with Q203 sterilizes in vitro cultures in 14 days. Synergy with Q203 occurs via direct inhibition of the cytochrome bd oxidase by HM2-16F. This study shows that amiloride derivatives represent a promising discovery platform for targeting energy generation in drug-resistant tuberculosis.
Publisher: Oxford University Press (OUP)
Date: 08-03-2015
DOI: 10.1093/JAC/DKV054
Abstract: It is not fully understood why inhibiting ATP synthesis in Mycobacterium species leads to death in non-replicating cells. We investigated the bactericidal mode of action of the anti-tubercular F1Fo-ATP synthase inhibitor bedaquiline (Sirturo™) in order to further understand the lethality of ATP synthase inhibition. Mycobacterium smegmatis strains were used for all the experiments. Growth and survival during a bedaquiline challenge were performed in multiple media types. A time-course microarray was performed during initial bedaquiline challenge in minimal medium. Oxygen consumption and proton-motive force measurements were performed on whole cells and inverted membrane vesicles, respectively. A killing of 3 log10 cfu/mL was achieved 4-fold more quickly in minimal medium (a glycerol carbon source) versus rich medium (LB with Tween 80) during bedaquiline challenge. Assessing the accelerated killing condition, we identified a transcriptional remodelling of metabolism that was consistent with respiratory dysfunction but inconsistent with ATP depletion. In glycerol-energized cell suspensions, bedaquiline caused an immediate 2.3-fold increase in oxygen consumption. Bedaquiline collapsed the transmembrane pH gradient, but not the membrane potential, in a dose-dependent manner. Both these effects were dependent on binding to the F1Fo-ATP synthase. Challenge with bedaquiline results in an electroneutral uncoupling of respiration-driven ATP synthesis. This may be a determinant of the bactericidal effects of bedaquiline, while ATP depletion may be a determinant of its delayed onset of killing. We propose that bedaquiline binds to and perturbs the a-c subunit interface of the Fo, leading to futile proton cycling, which is known to be lethal to mycobacteria.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2022
Publisher: Proceedings of the National Academy of Sciences
Date: 03-03-2014
Abstract: Molecular hydrogen is present in trace concentrations in the Earth’s lower atmosphere and is rapidly turned over through a biogeochemical cycle. Microbial soil processes are responsible for the majority of net uptake of H 2 from the atmosphere, but the enzymes involved have remained elusive. In this communication, we use genetic dissection and GC measurements to show that the soil actinobacterium Mycobacterium smegmatis can oxidize trace concentrations of H 2 . This process depends on two oxygen-dependent, membrane-associated [NiFe] hydrogenases with picomolar thresholds. Activity is most pronounced during carbon limitation, suggesting that mycobacteria oxidize a dependable trace gas to survive starvation. We propose that these enzymes and their homologs in other actinobacteria and soil phyla constitute the principal sink of global atmospheric H 2 .
Publisher: IEEE
Date: 02-2015
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
Publisher: Public Library of Science (PLoS)
Date: 24-07-2014
Publisher: American Society for Microbiology
Date: 19-05-2017
DOI: 10.1128/MICROBIOLSPEC.TBTB2-0014-2016
Abstract: The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. The Mycobacterium tuberculosis complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. Two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the absence of growth. M. tuberculosis is an obligately aerobic heterotroph that depends on oxidative phosphorylation for growth and survival. However, several studies are redefining the metabolic breadth of the genus. Alternative electron donors and acceptors may provide the maintenance energy for the pathogen to maintain viability in hypoxic, nonreplicating states relevant to latent infection. This hidden metabolic flexibility may ultimately decrease the efficacy of drugs targeted against primary dehydrogenases and terminal oxidases. However, it may also open up opportunities to develop novel antimycobacterials targeting persister cells. In this review, we discuss the progress in understanding the role of energetic targets in mycobacterial physiology and pathogenesis and the opportunities for drug discovery.
Publisher: Elsevier
Date: 2014
DOI: 10.1016/BS.AMPBS.2014.08.001
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 ex le, how Salmonella enterica and C ylobacter 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.
Publisher: Proceedings of the National Academy of Sciences
Date: 21-07-2014
Abstract: Obligate aerobes require survival strategies to persist in temporarily oxygen-deprived environments. In this article, we reveal a previously unidentified survival mechanism for obligately aerobic bacteria. Under oxygen-limiting conditions, the saprophytic actinomycete Mycobacterium smegmatis can rapidly switch between fermentative hydrogen production and hydrogen oxidation coupled to either oxygen or fumarate reduction depending on electron acceptor availability. To our knowledge, these results demonstrate for the first time (i) hydrogen production in an obligate aerobe, (ii) the unambiguous confirmation of fermentation in a mycobacterium and (iii) strong evidence that hydrogen has a role in survival and not just growth.
Publisher: American Society for Microbiology
Date: 15-02-2015
DOI: 10.1128/AEM.03364-14
Abstract: We have known for 40 years that soils can consume the trace amounts of molecular hydrogen (H 2 ) found in the Earth's atmosphere. This process is predicted to be the most significant term in the global hydrogen cycle. However, the organisms and enzymes responsible for this process were only recently identified. Pure culture experiments demonstrated that several species of Actinobacteria , including streptomycetes and mycobacteria, can couple the oxidation of atmospheric H 2 to the reduction of ambient O 2 . A combination of genetic, biochemical, and phenotypic studies suggest that these organisms primarily use this fuel source to sustain electron input into the respiratory chain during energy starvation. This process is mediated by a specialized enzyme, the group 5 [NiFe]-hydrogenase, which is unusual for its high affinity, oxygen insensitivity, and thermostability. Atmospheric hydrogen scavenging is a particularly dependable mode of energy generation, given both the ubiquity of the substrate and the stress tolerance of its catalyst. This minireview summarizes the recent progress in understanding how and why certain organisms scavenge atmospheric H 2 . In addition, it provides insight into the wider significance of hydrogen scavenging in global H 2 cycling and soil microbial ecology.
Location: Iran (Islamic Republic of)
No related grants have been discovered for Michael Berney.