scholarly journals Nitric oxide-dependent electron transport chain inhibition by the cytochrome bc 1 inhibitor and pretomanid combination kills Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Sheng Zeng ◽  
Jingran Zhang ◽  
Mingwei Sun ◽  
Xiaofei Zhang ◽  
Gregory M. Cook ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Light Emission ◽  
Bactericidal Effect ◽  
No Donor ◽  
No Donors ◽  
Transport Chain

Mycobacterium tuberculosis ( Mtb ), the causative agent of human tuberculosis, harbors a branched electron transport chain preventing the bactericidal action of cytochrome bc 1 inhibitors (e.g. TB47). Here, we investigated, using luminescent mycobacterial strains, the in vitro combination activity of cytochrome bc 1 inhibitors and nitric oxide (NO) donors including pretomanid (PMD) and explored the mechanisms of combination activity. The TB47 and PMD combination quickly abolished the light emission of luminescent bacilli, as was the case for the combination of TB47 and aurachin D, a putative cytochrome bd inhibitor. The TB47 and PMD combination inhibited Mtb oxygen consumption, decreased ATP levels, and had a delayed bactericidal effect. The NO scavenger carboxy-PTIO prevented the bactericidal activity of the drug combination, suggesting the requirement for NO. In addition, cytochrome bc 1 inhibitors were largely bactericidal when administered with DETA NONOate, another NO donor. Proteomic analysis revealed that the cotreated bacilli had a compromised expression of the dormancy regulon proteins, PE/PPE proteins and proteins required for the biosynthesis of several cofactors, including mycofactocin. Some of these proteomic changes, e.g. the impaired dormancy regulon induction, were attributed to PMD. In conclusion, combination of cytochrome bc 1 inhibitors with PMD inhibited Mtb respiration and killed the bacilli. The activity of cytochrome bc 1 inhibitors can be greatly enhanced by NO donors. Monitoring of luminescence may be further exploited to screen cytochrome bd inhibitors.

scholarly journals Nitric Oxide Protects Bacteria from Aminoglycosides by Blocking the Energy-Dependent Phases of Drug Uptake

2011 ◽  
Vol 55 (5) ◽  
pp. 2189-2196 ◽  
Author(s):  
Bruce D. McCollister ◽  
Matthew Hoffman ◽  
Maroof Husain ◽  
Andrés Vázquez-Torres
Keyword(s):  
Nitric Oxide ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Respiratory Activity ◽  
Inflammatory Responses ◽  
Drug Uptake ◽  
No Donor ◽  
Content Type ◽  
Transport Chain ◽  
Energy Dependent

ABSTRACTOur investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protectSalmonellaspp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellularSalmonellaagainst the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressedSalmonellarespiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen inSalmonella, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogensPseudomonas aeruginosaandStaphylococcus aureus. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria.

scholarly journals Identification of 4-Amino-Thieno[2,3-d]Pyrimidines as QcrB Inhibitors in Mycobacterium tuberculosis

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Gregory A. Harrison ◽  
Anne E. Mayer Bridwell ◽  
Megh Singh ◽  
Keshav Jayaraman ◽  
Leslie A. Weiss ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Drug Target ◽  
Drug Targets ◽  
Bacterial Infections ◽  
Nonsynonymous Mutation ◽  
Content Type ◽  
Transport Chain

ABSTRACT Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by Mycobacterium tuberculosis. Of the 10 million cases of tuberculosis in 2017, approximately 19% of new cases and 43% of previously treated cases were caused by strains of M. tuberculosis resistant to at least one frontline antibiotic. There is a clear need for new therapies that target these genetically resistant strains. Here, we report the discovery of a new series of antimycobacterial compounds, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit the growth of M. tuberculosis. To elucidate the mechanism by which these compounds inhibit M. tuberculosis, we selected for mutants resistant to a representative 4-amino-thieno[2,3-d]pyrimidine and sequenced these strains to identify the mutations that confer resistance. We isolated a total of 12 resistant mutants, each of which harbored a nonsynonymous mutation in the gene qcrB, which encodes a subunit of the electron transport chain (ETC) enzyme cytochrome bc1 oxidoreductase, leading us to hypothesize that 4-amino-thieno[2,3-d]pyrimidines target this enzyme complex. We found that addition of 4-amino-thieno[2,3-d]pyrimidines to M. tuberculosis cultures resulted in a decrease in ATP levels, supporting our model that these compounds inhibit the M. tuberculosis ETC. Furthermore, 4-amino-thieno[2,3-d]pyrimidines had enhanced activity against a mutant of M. tuberculosis deficient in cytochrome bd oxidase, which is a hallmark of cytochrome bc1 inhibitors. Therefore, 4-amino-thieno[2,3-d]pyrimidines represent a novel series of QcrB inhibitors that build on the growing number of chemical scaffolds that are able to inhibit the mycobacterial cytochrome bc1 complex. IMPORTANCE The global tuberculosis (TB) epidemic has been exacerbated by the rise in drug-resistant TB cases worldwide. To tackle this crisis, it is necessary to identify new vulnerable drug targets in Mycobacterium tuberculosis, the causative agent of TB, and develop compounds that can inhibit the bacterium through novel mechanisms of action. The QcrB subunit of the electron transport chain enzyme cytochrome bc1 has recently been validated to be a potential drug target. In the current work, we report the discovery of a new class of QcrB inhibitors, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit M. tuberculosis growth in vitro. These compounds are chemically distinct from previously reported QcrB inhibitors, and therefore, 4-amino-thieno[2,3-d]pyrimidines represent a new scaffold that can be exploited to inhibit this drug target.

scholarly journals Studies on the Mechanism by Which Anaerobiosis Prevents Swelling of Mitochondria in Vitro: Effect of Electron Transport Chain Inhibitors

1959 ◽  
Vol 234 (8) ◽  
pp. 2176-2186 ◽  
Author(s):  
F. Edmund Hunter ◽  
Jerome F. Levy ◽  
Joan Fink ◽  
Beverly Schutz ◽  
Francisco Guerra ◽  
...  
Keyword(s):  
Electron Transport ◽  
Electron Transport Chain ◽  
Transport Chain ◽  
Vitro Effect

scholarly journals In vitro effect of globotriaosylceramide on electron transport chain complexes and redox parameters

2019 ◽  
Vol 91 (2) ◽  
Author(s):  
RAFAELA M. ALVARIZ ◽  
ISABEL T.D.S. MOREIRA ◽  
GABRIELA K. CURY ◽  
CARMEN R. VARGAS ◽  
ALETHÉA G. BARSCHAK
Keyword(s):  
Electron Transport ◽  
Electron Transport Chain ◽  
Chain Complexes ◽  
Transport Chain ◽  
Vitro Effect

scholarly journals H2S-stimulated bioenergetics in chicken erythrocytes and the underlying mechanism

2020 ◽  
Vol 319 (1) ◽  
pp. R69-R78
Author(s):  
Zhuping Jin ◽  
Quanxi Zhang ◽  
Eden Wondimu ◽  
Richa Verma ◽  
Ming Fu ◽  
...  
Keyword(s):  
Electron Transport ◽  
Mammalian Cells ◽  
Electron Transport Chain ◽  
Structural Integrity ◽  
Underlying Mechanism ◽  
Atp Content ◽  
Hypoxic Conditions ◽  
Transport Chain ◽  
Chicken Erythrocytes

The production of H2S and its effect on bioenergetics in mammalian cells may be evolutionarily preserved. Erythrocytes of birds, but not those of mammals, have a nucleus and mitochondria. In the present study, we report the endogenous production of H2S in chicken erythrocytes, which was mainly catalyzed by 3-mercaptopyruvate sulfur transferase (MST). ATP content of erythrocytes was increased by MST-generated endogenous H2S under normoxic, but not hypoxic, conditions. NaHS, a H2S salt, increased ATP content under normoxic, but not hypoxic, conditions. ATP contents in the absence or presence of NaHS were eliminated by different inhibitors for mitochondrial electron transport chain in chicken erythrocytes. Succinate and glutamine, but not glucose, increased ATP content. NaHS treatment similarly increased ATP content in the presence of glucose, glutamine, or succinate, respectively. Furthermore, the expression and activity of sulfide:quinone oxidoreductase were enhanced by NaHS. The structural integrity of chicken erythrocytes was largely maintained during 2-wk NaHS treatment in vitro, whereas most of the erythrocytes without NaHS treatment were lysed. In conclusion, H2S may regulate cellular bioenergetics as well as cell survival of chicken erythrocytes, in which the functionality of the electron transport chain is involved. H2S may have different regulatory roles and mechanisms in bioenergetics of mammalian and bird cells.

scholarly journals Interaction of nitric oxide with the components of the plant mitochondrial electron transport chain

2018 ◽  
Vol 69 (14) ◽  
pp. 3413-3424 ◽  
Author(s):  
Kapuganti Jagadis Gupta ◽  
Aprajita Kumari ◽  
Igor Florez-Sarasa ◽  
Alisdair R Fernie ◽  
Abir U Igamberdiev
Keyword(s):  
Nitric Oxide ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain

scholarly journals The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells

2011 ◽  
Vol 22 (13) ◽  
pp. 2235-2245 ◽  
Author(s):  
Zhongyan Zhang ◽  
Nobunao Wakabayashi ◽  
Junko Wakabayashi ◽  
Yasushi Tamura ◽  
Woo-Jin Song ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Electron Transport ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Electron Transport Chain ◽  
Chain Complex ◽  
Atp Production ◽  
Transport Chain

Previous studies using in vitro cell culture systems have shown the role of the dynamin-related GTPase Opa1 in apoptosis prevention and mitochondrial DNA (mtDNA) maintenance. However, it remains to be tested whether these functions of Opa1 are physiologically important in vivo in mammals. Here, using the Cre-loxP system, we deleted mouse Opa1 in pancreatic beta cells, in which glucose-stimulated ATP production in mitochondria plays a key role in insulin secretion. Beta cells lacking Opa1 maintained normal copy numbers of mtDNA; however, the amount and activity of electron transport chain complex IV were significantly decreased, leading to impaired glucose-stimulated ATP production and insulin secretion. In addition, in Opa1-null beta cells, cell proliferation was impaired, whereas apoptosis was not promoted. Consequently, mice lacking Opa1 in beta cells develop hyperglycemia. The data suggest that the function of Opa1 in the maintenance of the electron transport chain is physiologically relevant in beta cells.

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