scholarly journals Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into theStreptococcus agalactiaeRespiratory Chain and Is a Potential Drug Target

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Andrea M. Lencina ◽  
Thierry Franza ◽  
Matthew J. Sullivan ◽  
Glen C. Ulett ◽  
Deepak S. Ipe ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Drug Target ◽  
Nadh Dehydrogenase ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Intact Cells ◽  
Content Type ◽  
Oxygen Reductase ◽  
Tract Infections

ABSTRACTThe opportunistic pathogenStreptococcus agalactiaeis the major cause of meningitis and sepsis in a newborn’s first week, as well as a considerable cause of pneumonia, urinary tract infections, and sepsis in immunocompromised adults. This pathogen respires aerobically if heme and quinone are available in the environment, and a functional respiratory chain is required for full virulence. Remarkably, it is shown here that the entire respiratory chain ofS. agalactiaeconsists of only two enzymes, a type 2 NADH dehydrogenase (NDH-2) and a cytochromebdoxygen reductase. There are no respiratory dehydrogenases other than NDH-2 to feed electrons into the respiratory chain, and there is only one respiratory oxygen reductase to reduce oxygen to water. AlthoughS. agalactiaegrows well invitroby fermentative metabolism, it is shown here that the absence of NDH-2 results in attenuated virulence, as observed by reduced colonization in heart and kidney in a mouse model of systemic infection. The lack of NDH-2 in mammalian mitochondria and its important role for virulence suggest this enzyme may be a potential drug target. For this reason, in this study,S. agalactiaeNDH-2 was purified and biochemically characterized, and the isolated enzyme was used to screen for inhibitors from libraries of FDA-approved drugs. Zafirlukast was identified to successfully inhibit both NDH-2 activity and aerobic respiration in intact cells. This compound may be useful as a laboratory tool to inhibit respiration inS. agalactiaeand, since it has few side effects, it might be considered a lead compound for therapeutics development.IMPORTANCES. agalactiaeis part of the human intestinal microbiota and is present in the vagina of ~30% of healthy women. Although a commensal, it is also the leading cause of septicemia and meningitis in neonates and immunocompromised adults. This organism can aerobically respire, but only using external sources of heme and quinone, required to have a functional electron transport chain. Although bacteria usually have a branched respiratory chain with multiple dehydrogenases and terminal oxygen reductases, here we establish thatS. agalactiaeutilizes only one type 2 NADH dehydrogenase (NDH-2) and one cytochromebdoxygen reductase to perform respiration. NADH-dependent respiration plays a critical role in the pathogen in maintaining NADH/NAD+redox balance in the cell, optimizing ATP production, and tolerating oxygen. In summary, we demonstrate the essential role of NDH-2 in respiration and its contribution toS. agalactiaevirulence and propose it as a potential drug target.

scholarly journals Systems Analysis of NADH Dehydrogenase Mutants Reveals Flexibility and Limits of Pseudomonas taiwanensis VLB120’s Metabolism

2020 ◽  
Vol 86 (11) ◽  
Author(s):  
Salome C. Nies ◽  
Robert Dinger ◽  
Yan Chen ◽  
Gossa G. Wordofa ◽  
Mette Kristensen ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Large Scale ◽  
Nadh Dehydrogenase ◽  
Metabolic Flexibility ◽  
Second Phase ◽  
Content Type ◽  
Depth Analysis ◽  
Nadh Dehydrogenases ◽  
The Impact

ABSTRACT Obligate aerobic organisms rely on a functional electron transport chain for energy conservation and NADH oxidation. Because of this essential requirement, the genes of this pathway are likely constitutively and highly expressed to avoid a cofactor imbalance and energy shortage under fluctuating environmental conditions. We here investigated the essentiality of the three NADH dehydrogenases of the respiratory chain of the obligate aerobe Pseudomonas taiwanensis VLB120 and the impact of the knockouts of corresponding genes on its physiology and metabolism. While a mutant lacking all three NADH dehydrogenases seemed to be nonviable, the single or double knockout mutant strains displayed no, or only a weak, phenotype. Only the mutant deficient in both type 2 dehydrogenases showed a clear phenotype with biphasic growth behavior and a strongly reduced growth rate in the second phase. In-depth analyses of the metabolism of the generated mutants, including quantitative physiological experiments, transcript analysis, proteomics, and enzyme activity assays revealed distinct responses to type 2 and type 1 dehydrogenase deletions. An overall high metabolic flexibility enables P. taiwanensis to cope with the introduced genetic perturbations and maintain stable phenotypes, likely by rerouting of metabolic fluxes. This metabolic adaptability has implications for biotechnological applications. While the phenotypic robustness is favorable in large-scale applications with inhomogeneous conditions, the possible versatile redirecting of carbon fluxes upon genetic interventions can thwart metabolic engineering efforts. IMPORTANCE While Pseudomonas has the capability for high metabolic activity and the provision of reduced redox cofactors important for biocatalytic applications, exploitation of this characteristic might be hindered by high, constitutive activity of and, consequently, competition with the NADH dehydrogenases of the respiratory chain. The in-depth analysis of NADH dehydrogenase mutants of Pseudomonas taiwanensis VLB120 presented here provides insight into the phenotypic and metabolic response of this strain to these redox metabolism perturbations. This high degree of metabolic flexibility needs to be taken into account for rational engineering of this promising biotechnological workhorse toward a host with a controlled and efficient supply of redox cofactors for product synthesis.

The Prokaryotic FAD Synthetase Family: A Potential Drug Target

2013 ◽  
Vol 19 (14) ◽  
pp. 2637-2648 ◽  
Author(s):  
Ana Serrano ◽  
Patricia Ferreira ◽  
Marta Martinez-Julvez ◽  
Milagros Medina
Keyword(s):  
Drug Target ◽  
Potential Drug Target ◽  
Potential Drug

Bacterial Polyphosphate Kinases Revisited: Role in Pathogenesis and Therapeutic Potential

2019 ◽  
Vol 20 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Lalit Kumar Gautam ◽  
Prince Sharma ◽  
Neena Capalash
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Wide Distribution ◽  
Medical Community ◽  
Polyphosphate Kinase ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Resistant Strains ◽  
Structural Aspects

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.

Molecular Docking with Trehalose-6 Phosphate Phosphatase: A Potential Drug Target of Filaral Parasite ‘Brugia malayi’

2011 ◽  
Vol 8 (4) ◽  
pp. 363-370 ◽  
Author(s):  
Lakshminarayanan Karthik ◽  
Palayam Malathy ◽  
Annie Trinitta ◽  
Krishnasamy Gunasekaran
Keyword(s):  
Molecular Docking ◽  
Drug Target ◽  
Brugia Malayi ◽  
Potential Drug Target ◽  
Potential Drug

scholarly journals Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe

2021 ◽  
Author(s):  
Nattawadee Panyain ◽  
Aurélien Godinat ◽  
Aditya Raymond Thawani ◽  
Sofía Lachiondo-Ortega ◽  
Katie Mason ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Lung Fibrosis ◽  
Drug Target ◽  
Protein Profiling ◽  
Deubiquitinating Enzyme ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Bona Fide ◽  
Carboxy Terminal

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1...

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