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  • 1.
    Bueno, Emilio
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Pinedo, Victor
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Adaptation of Vibrio cholerae to Hypoxic Environments2020In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 11, article id 739Article, review/survey (Refereed)
    Abstract [en]

    Bacteria can colonize virtually any environment on Earth due to their remarkable capacity to detect and respond quickly and adequately to environmental stressors. Vibrio cholerae is a cosmopolitan bacterium that inhabits a vast range of environments. The V. cholerae life cycle comprises diverse environmental and infective stages. The bacterium is found in aquatic ecosystems both under free-living conditions or associated with a wide range of aquatic organisms, and some strains are also capable of causing epidemics in humans. In order to adapt between environments, V. cholerae possesses a versatile metabolism characterized by the rapid cross-regulation of energy-producing pathways. Low oxygen concentration is a key environmental factor that governs V. cholerae physiology. This article reviews the metabolic plasticity that enables V. cholerae to thrive on low oxygen concentrations and its role in environmental and host adaptation.

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  • 2.
    Bueno, Emilio
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pinedo, Victor
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Shinde, Dhananjay D.
    Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Centergrid.266813.8, NE, Omaha, United States.
    Mateus, André
    Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Typas, Athanasios
    Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Savitski, Mikhail M.
    Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
    Thomas, Vinai C.
    Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Centergrid.266813.8, NE, Omaha, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Transient glycolytic complexation of arsenate enhances resistance in the enteropathogen Vibrio cholerae2022In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 5, article id e0165422Article in journal (Refereed)
    Abstract [en]

    The ubiquitous presence of toxic arsenate (AsV) in the environment has raised mechanisms of resistance in all living organisms. Generally, bacterial detoxification of AsV relies on its reduction to arsenite (AsIII) by ArsC, followed by the export of AsIII by ArsB. However, how pathogenic species resist this metalloid remains largely unknown. Here, we found that Vibrio cholerae, the etiologic agent of the diarrheal disease cholera, outcompetes other enteropathogens when grown on millimolar concentrations of AsV. To do so, V. cholerae uses, instead of ArsCB, the AsV-inducible vc1068-1071 operon (renamed var for vibrio arsenate resistance), which encodes the arsenate repressor ArsR, an alternative glyceraldehyde-3-phosphate dehydrogenase, a putative phosphatase, and the AsV transporter ArsJ. In addition to Var, V. cholerae induces oxidative stress-related systems to counter reactive oxygen species (ROS) production caused by intracellular AsV. Characterization of the var mutants suggested that these proteins function independently from one another and play critical roles in preventing deleterious effects on the cell membrane potential and growth derived from the accumulation AsV. Mechanistically, we demonstrate that V. cholerae complexes AsV with the glycolytic intermediate 3-phosphoglycerate into 1-arseno-3-phosphoglycerate (1As3PG). We further show that 1As3PG is not transported outside the cell; instead, it is subsequently dissociated to enable extrusion of free AsV through ArsJ. Collectively, we propose the formation of 1As3PG as a transient metabolic storage of AsV to curb the noxious effect of free AsV. This study advances our understanding of AsV resistance in bacteria and underscores new points of vulnerability that might be an attractive target for antimicrobial interventions. IMPORTANCE Even though resistance to arsenate has been extensively investigated in environmental bacteria, how enteric pathogens tolerate this toxic compound remains unknown. Here, we found that the cholera pathogen V. cholerae exhibits increased resistance to arsenate compared to closely related enteric pathogens. Such resistance is promoted not by ArsC-dependent reduction of arsenate to arsenite but by an operon encoding an arsenate transporter (ArsJ), an alternative glyceraldehyde 3-phosphate dehydrogenase (VarG), and a putative, uncharacterized phosphatase (VarH). Mechanistically, we demonstrate that V. cholerae detoxifies arsenate by complexing it with the glycolytic intermediate 3-phosphoglycerate into 1-arseno-3-phosphoglycerate (1As3PG). 1As3PG is not transported outside the cell; instead, it is subsequently dissociated by VarH to enable extrusion of free arsenate through ArsJ. Collectively, this study proposes a novel mechanism for arsenate detoxification, entirely independent of arsenate reduction and arsenite extrusion, that enhances V. cholerae resistance to this metalloid compared to other enteric pathogens.

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  • 3.
    Bueno, Emilio
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). CSIC, Estac Expt Zaidin, Dept Soil Microbiol & Symbiot Syst, C Profesor Albareda 1, E-18008 Granada, Spain.
    Robles, Eloy F.
    Torres, Maria J.
    Krell, Tino
    Bedmar, Eulogio J.
    Delgado, Maria J.
    Mesa, Socorro
    Disparate response to microoxia and nitrogen oxides of the Bradyrhizobium japonicum napEDABC, nirK and norCBQD denitrification genes2017In: Nitric oxide, ISSN 1089-8603, E-ISSN 1089-8611, Vol. 68, p. 137-149Article in journal (Refereed)
    Abstract [en]

    Expression of the Bradyrhizobium japonicum napEDABC, nirK and norCBQD denitrification genes requires low oxygen (O-2) tension and nitrate (NO3), through a regulatory network comprised of two coordinated cascades, FixLJ-FixK(2)-NnrR and RegSR-NifA. To precisely understand how these signals are integrated in the FixLJ-FixK(2)-NnrR circuit, we analyzed beta-Galactosidase activities from napE-lacZ, nirK-lacZ and norC-lacZ fusions, and performed analyses of NapC and NorC levels as well as periplasmic nitrate reductase (Nap) activity, in B. japonicum wildtype and fixK(2) and nnrR mutant backgrounds. While microoxic conditions (2% O-2 at headspace) were sufficient to induce expression of napEDABC and nirK genes and this control depends on FixK(2), norCBQD expression requires, in addition to microoxia, nitric oxide gas (NO) and both FixK(2) and NnrR transcription factors. Purified FixK(2) protein directly interacted and activated transcription in collaboration with B. japonicum RNA polymerase (RNAP) from the napEDABC and nirK promoters, but not from the norCBQD promoter. Further, recombinant NnrR protein bound exclusively to the norCBQD promoter in an O-2-sensitive manner. Our work suggest a disparate regulation of B. japonicum denitrifying genes expression with regard to their dependency to microoxia, nitrogen oxides (NOx), and the regulatory proteins FixK(2) and NnrR. In this control, expression of napEDABC and nirK genes requires microoxic conditions and directly depends on FixK2, while expression of norCBQD genes relies on NO, being NnrR the candidate which directly interacts with the norCBQD promoter. 

  • 4.
    Bueno, Emilio
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sit, Brandon
    Waldor, Matthew K.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Anaerobic nitrate reduction divergently governs population expansion of the enteropathogen Vibrio cholerae2018In: Nature Microbiology, E-ISSN 2058-5276, Vol. 3, no 12, p. 1346-1353Article in journal (Refereed)
    Abstract [en]

    To survive and proliferate in the absence of oxygen, many enteric pathogens can undergo anaerobic respiration within the host by using nitrate (NO3-) as an electron acceptor(1,2). In these bacteria, NO3- is typically reduced by a nitrate reductase to nitrite (NO2-), a toxic intermediate that is further reduced by a nitrite reductase(3). However, Vibrio cholerae, the intestinal pathogen that causes cholera, lacks a nitrite reductase, leading to NO2- accumulation during nitrate reduction 4(.) Thus, V. cholerae is thought to be unable to undergo NO3-(-)dependent anaerobic respiration(4). Here, we show that during hypoxic growth, NO3- reduction in V. cholerae divergently affects bacterial fitness in a manner dependent on environmental pH. Remarkably, in alkaline conditions, V. cholerae can reduce NO3- to support population growth. Conversely, in acidic conditions, accumulation of NO2- from NO3- reduction simultaneously limits population expansion and preserves cell viability by lowering fermentative acid production. Interestingly, other bacterial species such as Salmonella typhimurium, enterohaemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium also reproduced this pH-dependent response, suggesting that this mechanism might be conserved within enteric pathogens. Our findings explain how a bacterial pathogen can use a single redox reaction to divergently regulate population expansion depending on the fluctuating environmental pH.

  • 5.
    Bueno, Emilio
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sit, Brandon
    Waldor, Matthew K.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Genetic Dissection of the Fermentative and Respiratory Contributions Supporting Vibrio cholerae Hypoxic Growth2020In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 202, no 24, article id e00243-20Article in journal (Refereed)
    Abstract [en]

    Both fermentative and respiratory processes contribute to bacterial metabolic adaptations to low oxygen tension (hypoxia). In the absence of O-2 as a respiratory electron sink, many bacteria utilize alternative electron acceptors, such as nitrate (NO3-). During canonical NO3- respiration, NO3- is reduced in a stepwise manner to N-2 by a dedicated set of reductases. Vibrio cholerae, the etiological agent of cholera, requires only a single periplasmic NO3- reductase (NapA) to undergo NO3- respiration, suggesting that the pathogen possesses a noncanonical NO3- respiratory chain. In this study, we used complementary transposon-based screens to identify genetic determinants of general hypoxic growth and NO3- respiration in V. cholerae. We found that while the V. cholerae NO3- respiratory chain is primarily composed of homologues of established NO3- respiratory genes, it also includes components previously unlinked to this process, such as the Na+-NADH dehydrogenase Nqr. The ethanol-generating enzyme AdhE was shown to be the principal fermentative branch required during hypoxic growth in V. cholerae. Relative to single adhE or napA mutant strains, a V. cholerae strain lacking both genes exhibited severely impaired hypoxic growth in vitro and in vivo. Our findings reveal the genetic basis of a specific interaction between disparate energy production pathways that supports pathogen fitness under shifting conditions. Such metabolic specializations in V. cholerae and other pathogens are potential targets for antimicrobial interventions.

    IMPORTANCE Bacteria reprogram their metabolism in environments with low oxygen levels (hypoxia). Typically, this occurs via regulation of two major, but largely independent, metabolic pathways: fermentation and respiration. In this study, we found that the diarrheal pathogen Vibrio cholerae has a respiratory chain for NO3- that consists largely of components found in other NO3- respiratory systems but also contains several proteins not previously linked to this process. Both AdhE-dependent fermentation and NO3- respiration were required for efficient pathogen growth under both laboratory conditions and in an animal infection model. These observations provide a specific example of fermentative respiratory interactions and identify metabolic vulnerabilities that may be targetable for new antimicrobial agents in V. cholerae and related pathogens.

  • 6.
    Campbell, Christopher
    et al.
    Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
    Fingleton, Claire
    Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
    Zeden, Merve S.
    Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gallagher, Laura A.
    Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
    Shinde, Dhananjay
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Ahn, Jongsam
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Olson, Heather M.
    Biological Sciences Division, Pacific Northwest National Laboratory, WA, Richland, United States.
    Fillmore, Thomas L.
    Biological Sciences Division, Pacific Northwest National Laboratory, WA, Richland, United States.
    Adkins, Joshua N.
    Biological Sciences Division, Pacific Northwest National Laboratory, WA, Richland, United States.
    Razvi, Fareha
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Bayles, Kenneth W.
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Fey, Paul D.
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Thomas, Vinai C.
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Clair, Geremy C.
    Biological Sciences Division, Pacific Northwest National Laboratory, WA, Richland, United States.
    O’gara, James P.
    Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland.
    Accumulation of succinyl coenzyme a perturbs the methicillin-resistant staphylococcus aureus (Mrsa) succinylome and is associated with increased susceptibility to beta-lactam antibiotics2021In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 12, no 3, article id e00530-21Article in journal (Refereed)
    Abstract [en]

    Penicillin binding protein 2a (PBP2a)-dependent resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is regulated by the activity of the tricarboxylic acid (TCA) cycle via a poorly understood mechanism. We report that mutations in sucC and sucD, but not other TCA cycle enzymes, negatively impact β-lactam resistance without changing PBP2a expression. Increased intracellular levels of succinyl coenzyme A (succinyl-CoA) in the sucC mutant significantly perturbed lysine succinylation in the MRSA proteome. Suppressor mutations in sucA or sucB, responsible for succinyl-CoA biosynthesis, reversed sucC mutant phenotypes. The major autolysin (Atl) was the most succinylated protein in the proteome, and increased Atl succinylation in the sucC mutant was associated with loss of autolytic activity. Although PBP2a and PBP2 were also among the most succinylated proteins in the MRSA proteome, peptidoglycan architecture and cross-linking were unchanged in the sucC mutant. These data reveal that perturbation of the MRSA succinylome impacts two interconnected cell wall phenotypes, leading to repression of autolytic activity and increased susceptibility to β-lactam antibiotics.

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  • 7. Felgner, S
    et al.
    Frahm, M
    Kocijancic, D
    Rohde, M
    Eckweiler, D
    Bielecka, A
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Abraham, WR
    Curtiss, R
    Häussler, S
    Erhardt, M
    Weiss, S
    aroA-Deficient Salmonella enterica Serovar Typhimurium Is More Than a Metabolically Attenuated Mutant2016In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 7, no 5, article id e01220-16Article in journal (Refereed)
    Abstract [en]

    Recombinant attenuated Salmonella enterica serovar Typhimurium strains are believed to act as powerful live vaccine carriers that are able to elicit protection against various pathogens. Auxotrophic mutations, such as a deletion of aroA, are commonly introduced into such bacteria for attenuation without incapacitating immunostimulation. In this study, we describe the surprising finding that deletion of aroA dramatically increased the virulence of attenuated Salmonella in mouse models. Mutant bacteria lacking aroA elicited increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) after systemic application. A detailed genetic and phenotypic characterization in combination with transcriptomic and metabolic profiling demonstrated that Delta aroA mutants display pleiotropic alterations in cellular physiology and lipid and amino acid metabolism, as well as increased sensitivity to penicillin, complement, and phagocytic uptake. In concert with other immunomodulating mutations, deletion of aroA affected flagellin phase variation and gene expression of the virulence-associated genes arnT and ansB. Finally, Delta aroA strains displayed significantly improved tumor therapeutic activity. These results highlight the importance of a functional shikimate pathway to control homeostatic bacterial physiology. They further highlight the great potential of Delta aroA-attenuated Salmonella for the development of vaccines and cancer therapies with important implications for host-pathogen interactions and translational medicine. 

    IMPORTANCE Recombinant attenuated bacterial vector systems based on genetically engineered Salmonella have been developed as highly potent vaccines. Due to the pathogenic properties of Salmonella, efficient attenuation is required for clinical applications. Since the hallmark study by Hoiseth and Stocker in 1981 (S. K. Hoiseth and B. A. D. Stocker, Nature 291:238-239, 1981, http://dx.doi.org/10.1038/291238a0), the auxotrophic Delta aroA mutation has been generally considered safe and universally used to attenuate bacterial strains. Here, we are presenting the remarkable finding that a deletion of aroA leads to pronounced alterations of gene expression, metabolism, and cellular physiology, which resulted in increased immunogenicity, virulence, and adjuvant potential of Salmonella. These results suggest that the enhanced immunogenicity of aroA-deficient Salmonella strains might be advantageous for optimizing bacterial vaccine carriers and immunotherapy. Accordingly, we demonstrate a superior performance of Delta aroA Salmonella in bacterium-mediated tumor therapy. In addition, the present study highlights the importance of a functional shikimate pathway to sustain bacterial physiology and metabolism.

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  • 8. Jiménez-Leiva, Andrea
    et al.
    Cabrera, Juan J.
    Bueno, Emilio
    Department of Soil Microbiology and Symbiotic Systems, Estación Experimental del Zaidín, Consejo Superior de Investigaciones Científicas, Granada, Spain.
    Torres, María J.
    Salazar, Sergio
    Bedmar, Eulogio J.
    Delgado, María J.
    Mesa, Socorro
    Expanding the regulon of the Bradyrhizobium diazoefficiens NnrR transcription factor: new insights into the denitrification pathway2019In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 10, article id 1926Article in journal (Refereed)
    Abstract [en]

    Denitrification in the soybean endosymbiont Bradyrhizobium diazoefficiens is controlled by a complex regulatory network composed of two hierarchical cascades, FixLJ-FixK(2)-NnrR and RegSR-NifA. In the former cascade, the CRP/FNR-type transcription factors FixK(2) and NnrR exert disparate control on expression of core denitrifying systems encoded by napEDABC, nirK, norCBQD, and nosRZDFYLX genes in response to microoxia and nitrogen oxides, respectively. To identify additional genes controlled by NnrR and involved in the denitrification process in B. diazoefficiens, we compared the transcriptional profile of an nnrR mutant with that of the wild type, both grown under anoxic denitrifying conditions. This approach revealed more than 170 genes were simultaneously induced in the wild type and under the positive control of NnrR. Among them, we found the cycA gene which codes for the c(550) soluble cytochrome (CycA), previously identified as an intermediate electron donor between the bc(1) complex and the denitrifying nitrite reductase NirK. Here, we demonstrated that CycA is also required for nitrous oxide reductase activity. However, mutation in cycA neither affected nosZ gene expression nor NosZ protein steady-state levels. Furthermore, cycA, nnrR and its proximal divergently oriented nnrS gene, are direct targets for FixK(2) as determined by in vitro transcription activation assays. The dependence of cycA expression on FixK(2) and NnrR in anoxic denitrifying conditions was validated at transcriptional level, determined by quantitative reverse transcription PCR, and at the level of protein by performing heme c-staining of soluble cytochromes. Thus, this study expands the regulon of NnrR and demonstrates the role of CycA in the activity of the nitrous oxide reductase, the key enzyme for nitrous oxide mitigation.

  • 9.
    Ritzl-Rinkenberger, Barbara
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pinedo, Victor
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sun, Yingjie
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
    Garner, Ethan C.
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
    Mateus, André
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A novel penicillin-binding protein in Vibrio cholerae important for lipopolysaccharide homeostasisManuscript (preprint) (Other academic)
  • 10.
    Sit, Brandon
    et al.
    Division of Infectious Diseases, Brigham and Women’s Hospital, MA, Boston, United States; Department of Microbiology, Harvard Medical School, MA, Boston, United States; Department of Biology, Massachusetts Institute of Technology, MA, Cambridge, United States.
    Srisuknimit, Veerasak
    Division of Infectious Diseases, Brigham and Women’s Hospital, MA, Boston, United States; Department of Microbiology, Harvard Medical School, MA, Boston, United States; Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Zingl, Franz G.
    Division of Infectious Diseases, Brigham and Women’s Hospital, MA, Boston, United States; Department of Microbiology, Harvard Medical School, MA, Boston, United States.
    Hullahalli, Karthik
    Division of Infectious Diseases, Brigham and Women’s Hospital, MA, Boston, United States; Department of Microbiology, Harvard Medical School, MA, Boston, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldor, Matthew K.
    Division of Infectious Diseases, Brigham and Women’s Hospital, MA, Boston, United States; Department of Microbiology, Harvard Medical School, MA, Boston, United States; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, MA, Boston, United States; Howard Hughes Medical Institute, MD, Bethesda, United States.
    Undecaprenyl phosphate translocases confer conditional microbial fitness2023In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 613, no 7945, p. 721-728Article in journal (Refereed)
    Abstract [en]

    The microbial cell wall is essential for maintenance of cell shape and resistance to external stressors1. The primary structural component of the cell wall is peptidoglycan, a glycopolymer with peptide crosslinks located outside of the cell membrane1. Peptidoglycan biosynthesis and structure are responsive to shifting environmental conditions such as pH and salinity2–6, but the mechanisms underlying such adaptations are incompletely understood. Precursors of peptidoglycan and other cell surface glycopolymers are synthesized in the cytoplasm and then delivered across the cell membrane bound to the recyclable lipid carrier undecaprenyl phosphate7 (C55-P, also known as UndP). Here we identify the DUF368-containing and DedA transmembrane protein families as candidate C55-P translocases, filling a critical gap in knowledge of the proteins required for the biogenesis of microbial cell surface polymers. Gram-negative and Gram-positive bacteria lacking their cognate DUF368-containing protein exhibited alkaline-dependent cell wall and viability defects, along with increased cell surface C55-P levels. pH-dependent synthetic genetic interactions between DUF368-containing proteins and DedA family members suggest that C55-P transporter usage is dynamic and modulated by environmental inputs. C55-P transporter activity was required by the cholera pathogen for growth and cell shape maintenance in the intestine. We propose that conditional transporter reliance provides resilience in lipid carrier recycling, bolstering microbial fitness both inside and outside the host.

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  • 11. Torres, Maria J.
    et al.
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). CSIC, Estn Expt Zaidin, Dept Soil Microbiol & Symbiot Syst, Granada, Spain.
    Jimenez-Leiva, Andrea
    Cabrera, Juan J.
    Bedmar, Eulogio J.
    Mesa, Socorro
    Delgado, Maria J.
    FixK(2) Is the Main Transcriptional Activator of Bradyrhizobium diazoefficiens nosRZDYFLX Genes in Response to Low Oxygen2017In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 8, article id 1621Article in journal (Refereed)
    Abstract [en]

    The powerful greenhouse gas, nitrous oxide (N2O) has a strong potential to drive climate change. Soils are the major source of N2O and microbial nitrification and denitrification the main processes involved. The soybean endosymbiont Bradyrhizobium diazoefficiens is considered a model to study rhizobial denitrification, which depends on the napEDABC, nirK, norCBQD, and nosRZDYFLX genes. In this bacterium, the role of the regulatory cascade FixLJ-FixK(2)-NnrR in the expression of napEDABC, nirK, and norCBQD genes involved in N2O synthesis has been previously unraveled. However, much remains to be discovered regarding the regulation of the respiratory N2O reductase (N2OR), the key enzyme that mitigates N2O emissions. In this work, we have demonstrated that nosRZDYFLX genes constitute an operon which is transcribed from a major promoter located upstream of the nosR gene. Low oxygen was shown to be the main inducer of expression of nosRZDYFLX genes and N2OR activity, FixK(2) being the regulatory protein involved in such control. Further, by using an in vitro transcription assay with purified FixK(2) protein and B. diazoefficiens RNA polymerase we were able to show that the nosRZDYFLX genes are direct targets of FixK(2).

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  • 12.
    Zeden, Merve S.
    et al.
    Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
    Gallagher, Laura A.
    Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nolan, Aaron C.
    Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
    Ahn, Jongsam
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Shinde, Dhananjay
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Razvi, Fareha
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Sladek, Margaret
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Burke, Órla
    Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
    O'Neill, Eoghan
    Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Fey, Paul D.
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Thomas, Vinai C.
    Department of Pathology and Microbiology, University of Nebraska Medical Center, NE, Omaha, United States.
    O'Gara, James P.
    Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
    Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics2023In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 7, article id e1011536Article in journal (Refereed)
    Abstract [en]

    Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant.

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