Positions

Overview

  • One of the most prominent features of M. tuberculosis is its unusual outer membrane that plays a crucial role in the intrinsic drug resistance and in survival of M. tuberculosis in vivo. This membrane is functionalized by intriguing proteins which provide essential functions such as nutrient uptake, have new structures and likely function by novel mechanisms. We discovered the first outer membrane channel protein in mycobacteria, obtained the first crystal structure of a mycobacterial outer membrane protein and demonstrated that mycobacteria indeed have two membranes. Our goal is to identify and characterize outer membrane proteins of M. tuberculosis. One of those proteins, CpnT, enables the secretion of the major exotoxin of M. tuberculosis, a NAD+ glycohydrolase which triggers necroptosis in infected macrophages. We use state-of-the art genetic, biochemical and biophysical approaches to achieve our aims.

    • Selected Publications

    Academic Article

    Year Title Altmetric
    2020 Cryo-EM structure of arabinosyltransferase EmbB from Mycobacterium smegmatis.  Nature Communications.  11. 2020
    2020 Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection.  Nature Communications.  11. 2020
    2020 Comprehensive analysis of iron utilization by Mycobacterium tuberculosis.  PLoS Pathogens.  16. 2020
    2020 NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages.  Cellular Microbiology.  22. 2020
    2019 Heme and hemoglobin utilization by Mycobacterium tuberculosis.  Nature Communications.  10. 2019
    2019 A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity.  Genes.  10. 2019
    2019 A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity 2019
    2019 The tuberculosis necrotizing toxin is an NAD and NADP glycohydrolase with distinct enzymatic properties.  Journal of Biological Chemistry.  294:3024-3036. 2019
    2019 A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis.  Antimicrobial Agents and Chemotherapy.  63. 2019
    2018 NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis.  Cell Reports.  24:429-440. 2018
    2017 PPE surface proteins are required for heme utilization by Mycobacterium tuberculosis.  mBio.  8. 2017
    2016 A Macrophage Infection Model to Predict Drug Efficacy Against Mycobacterium Tuberculosis.  ASSAY and Drug Development Technologies.  14:345-354. 2016
    2016 Hetero-oligomeric MspA pores in Mycobacterium smegmatis.  FEMS Microbiology Letters.  363. 2016
    2016 Protein phosphatase, Mg2+/Mn2+-dependent 1A controls the innate antiviral and antibacterial response of macrophages during HIV-1 and Mycobacterium tuberculosis infection.  Oncotarget.  7:15394-15409. 2016
    2016 Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence 2016
    2015 The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD 2015
    2015 Surface hydrolysis of sphingomyelin by the outer membrane protein Rv0888 supports replication of Mycobacterium tuberculosis in macrophages 2015
    2015 Disulfiram and copper ions kill Mycobacterium tuberculosis in a synergistic manner.  Antimicrobial Agents and Chemotherapy.  59:4835-4844. 2015
    2015 The mycobacterium tuberculosis outer membrane channel protein CpnT confers susceptibility to toxic molecules.  Antimicrobial Agents and Chemotherapy.  59:2328-2336. 2015
    2015 Mycobacteria, metals, and the macrophage.  Immunological Reviews.  264:249-263. 2015
    2014 An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity 2014
    2014 Role of the Mce1 transporter in the lipid homeostasis of Mycobacterium tuberculosis.  Tuberculosis.  94:170-177. 2014
    2014 Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling 2014
    2014 Organ pathology in the absence of bacteria?.  Journal of Infectious Diseases.  209:971. 2014
    2014 The progression of cell death affects the rejection of allogeneic tumors in immune-competent mice - implications for cancer therapy.  Frontiers in Immunology.  5. 2014
    2013 Porins increase copper susceptibility of Mycobacterium tuberculosis.  Journal of Bacteriology.  195:5133-5140. 2013
    2013 A multicopper oxidase is required for copper resistance in mycobacterium tuberculosis.  Journal of Bacteriology.  195:3724-3733. 2013
    2013 Mycobacterium tuberculosis is resistant to streptolydigin.  Tuberculosis.  93:401-404. 2013
    2013 Copper-boosting compounds: A novel concept for antimycobacterial drug discovery.  Antimicrobial Agents and Chemotherapy.  57:1089-1091. 2013
    2013 Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis.  PLoS Pathogens.  9. 2013
    2013 Updating and curating metabolic pathways of TB.  Tuberculosis.  93:47-59. 2013
    2012 Ectoine biosynthesis in Mycobacterium smegmatis.  Applied and Environmental Microbiology.  78:7483-7486. 2012
    2012 Molecular dynamics study of MspA arginine mutants predicts slow DNA translocations and ion current blockades indicative of DNA sequence.  ACS Nano.  6:6960-6968. 2012
    2012 MspA nanopores from subunit dimers.  PLoS ONE.  7. 2012
    2012 Cathepsin G and neutrophil elastase contribute to lung-protective immunity against mycobacterial infections in mice.  Journal of Immunology.  188:4476-4487. 2012
    2012 Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload.  Tuberculosis.  92:202-210. 2012
    2012 Reading DNA at single-nucleotide resolution with a mutant MspA nanopore and phi29 DNA polymerase.  Nature Biotechnology.  30:349-353. 2012
    2012 Elucidation and chemical modulation of sulfolipid-1 biosynthesis in Mycobacterium tuberculosis.  Journal of Biological Chemistry.  287:7990-8000. 2012
    2012 Uptake of sulfate but not phosphate by Mycobacterium tuberculosis is slower than that for Mycobacterium smegmatis.  Journal of Bacteriology.  194:956-964. 2012
    2012 Molecular structure and peptidoglycan recognition of mycobacterium tuberculosis ArfA (Rv0899).  Journal of Molecular Biology.  416:208-220. 2012
    2012 Biological Nanopore MspA for DNA Sequencing.  Biophysical Journal.  102:203a-203a. 2012
    2011 Nucleotide discrimination with DNA immobilized in the MSPA nanopore.  PLoS ONE.  6. 2011
    2011 Expression of the ompATb operon accelerates ammonia secretion and adaptation of Mycobacterium tuberculosis to acidic environments 2011
    2011 Importance of porins for biocide efficacy against Mycobacterium smegmatis.  Applied and Environmental Microbiology.  77:3068-3073. 2011
    2011 Mycobacterium tuberculosis can utilize heme as an iron source.  Journal of Bacteriology.  193:1767-1770. 2011
    2011 Structure and Interactions of the M. tuberculosis Membrane Protein Virulence Factor Rv0899.  Biophysical Journal.  100:8a-8a. 2011
    2011 Copper resistance is essential for virulence of Mycobacterium tuberculosis 2011
    2010 Role of porins in iron uptake by Mycobacterium smegmatis.  Journal of Bacteriology.  192:6411-6417. 2010
    2010 Antimycobacterial activity in vitro of pigments isolated from Antarctic bacteria 2010
    2010 Taking phage integration to the next level as a genetic tool for mycobacteria.  Gene.  468:8-19. 2010
    2010 Nanopore DNA sequencing with MspA 2010
    2010 Hit-and-run stimulation: A novel concept to reactivate latent HIV-1 infection without cytokine gene induction.  Journal of Virology.  84:8712-8720. 2010
    2010 Mycobacterium tuberculosis Rv0899 Adopts a Mixed α/β-Structure and Does Not Form a Transmembrane β-Barrel.  Biochemistry.  49:2768-2777. 2010
    2010 Mycobacterial outer membranes: in search of proteins.  Trends in Microbiology.  18:109-116. 2010
    2010 Rapid evaluation of the Mycobactericidal efficacy of disinfectants in the quantitative carrier test EN 14563 by using fluorescent Mycobacterium terrae.  Applied and Environmental Microbiology.  76:546-554. 2010
    2010 Single Nucleotide Discrimination in Single Stranded DNA Immobilized within Biological Nanopore MspA.  Biophysical Journal.  98:600a-600a. 2010
    2010 Structure of the Mycobacterium Tuberculosis Virulence Factor Rv0899 (ompATb).  Biophysical Journal.  98:624a-625a. 2010
    2009 Construction of unmarked deletion mutants in mycobacteria..  Methods in Molecular Biology.  465:279-295. 2009
    2009 Poly-N-Isopropyl-acrylamide/acrylic acid copolymers for the generation of nanostructures on mica surfaces and as hydrophobic host systems for the porin mspa from mycobacterium smegmatis 2009
    2009 Decreased outer membrane permeability protects mycobacteria from killing by ubiquitin-derived peptides 2009
    2009 Porins facilitate nitric oxide-mediated killing of mycobacteria 2009
    2009 Functions of the periplasmic loop of the porin MspA from Mycobacterium smegmatis.  Journal of Biological Chemistry.  284:10223-10231. 2009
    2009 Direct observation of gold nanoparticle assemblies with the porin MspA on mica.  ACS Nano.  3:462-466. 2009
    2009 Nanopore Sequencing with MspA.  Biophysical Journal.  96:316a-316a. 2009
    2009 Physiology of Mycobacteria.  Advances in Microbial Physiology.  55. 2009
    2009 Role of porins in the susceptibility of Mycobacterium smegmatis and Mycobacterium chelonae to aldehyde-based disinfectants and drugs.  Antimicrobial Agents and Chemotherapy.  53:4015-4018. 2009
    2008 Single-molecule DNA detection with an engineered MspA protein nanopore 2008
    2008 Identification of outer membrane proteins of Mycobacterium tuberculosis.  Tuberculosis.  88:526-544. 2008
    2008 Role of porins for uptake of antibiotics by Mycobacterium smegmatis.  Antimicrobial Agents and Chemotherapy.  52:3127-3134. 2008
    2008 Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis.  Antimicrobial Agents and Chemotherapy.  52:2503-2511. 2008
    2008 Rv1698 of Mycobacterium tuberculosis represents a new class of channel-forming outer membrane proteins.  Journal of Biological Chemistry.  283:17827-17837. 2008
    2008 Disclosure of the mycobacterial outer membrane: Cryo-electron tomography and vitreous sections reveal the lipid bilayer structure 2008
    2008 Nutrient acquisition by mycobacteria..  Microbiology.  154:679-692. 2008
    2008 Construction of unmarked deletion mutants in mycobacteria.  Methods in Molecular Biology.  465:279-295. 2008
    2007 Functional expression of the Flp recombinase in Mycobacterium bovis BCG.  Gene.  399:112-119. 2007
    2007 A genomic view of sugar transport in Mycobacterium smegmatis and Mycobacterium tuberculosis.  Journal of Bacteriology.  189:5903-5915. 2007
    2007 Identification of two Mycobacterium smegmatis lipoproteins exported by a SecA2-dependent pathway.  Journal of Bacteriology.  189:5090-5100. 2007
    2007 Characterization of nanostructured surfaces generated by reconstitution of the porin MspA from Mycobacterium smegmatis.  Small.  3:1084-1097. 2007
    2007 Porins are required for uptake of phosphates by Mycobacterium smegmatis.  Journal of Bacteriology.  189:2435-2442. 2007
    2007 Expression of the major porin gene mspA is regulated in Mycobacterium smegmatis.  Journal of Bacteriology.  189:958-967. 2007
    2006 Nanoarray-surfaces by reconstitution of the porin MspA into stabilized long-chain-lipid-monolayers at a gold-surface.  Electroanalysis.  18:1859-1870. 2006
    2006 Topology of the porin MspA in the outer membrane of Mycobacterium smegmatis.  Journal of Biological Chemistry.  281:5908-5915. 2006
    2006 P6.26 GFP-Based Rapid Detection of the Mycobactericidal Efficacy of Disinfectants in the Quantitative Carrier Test prEN 14563.  Journal of Hospital Infection.  64:S39-S39. 2006
    2005 The growth rate of Mycobacterium smegmatis depends on sufficient porin-mediated influx of nutrients 2005
    2005 Erratum: MspA provides the main hydrophilic pathway through the cell wall of Mycobacterium smegmatis (Molecular Microbiology (2001) 40 (451-464)) 2005
    2005 Porins limit the intracellular persistence of Mycobacterium smegmatis.  Microbiology.  151:2403-2410. 2005
    2004 Consecutive gene deletions in Mycobacterium smegmatis using the yeast FLP recombinase.  Gene.  343:181-190. 2004
    2004 Identification and semi-quantitative analysis of Mycobacterium tuberculosis H37Rv ftsZ gene-specific promoter activity-containing regions.  Research in Microbiology.  155:817-826. 2004
    2004 DNA-free RNA preparations from mycobacteria.  BMC Microbiology.  4. 2004
    2004 Multidrug resistance of a porin deletion mutant of Mycobacterium smegmatis.  Antimicrobial Agents and Chemotherapy.  48:4163-4170. 2004
    2004 A recombinant bispecific single-chain Fv antibody against HLA class II and FcγRIII (CD16) triggers effective lysis of lymphoma cells.  British Journal of Haematology.  125:167-179. 2004
    2004 The Structure of a Mycobacterial Outer-Membrane Channel.  Science.  303:1189-1192. 2004
    2004 Efficient eukaryotic expression of fluorescent scFv fusion proteins directed against CD antigens for FACS applications.  Journal of Immunological Methods.  285:265-280. 2004
    2004 Reconstitution of a porin from Mycobacterium smegmatis at HOPG covered with hydrophobic host layers.  Surface and Interface Analysis.  36:127-134. 2004
    2004 The MspA porin promotes growth and increases antibiotic susceptibility of both Mycobacterium bovis BCG and Mycobacterium tuberculosis.  Microbiology.  150:853-864. 2004
    2003 The Phosphotransferase System of Streptomyces coelicolor Is Biased for N-Acetylglucosamine Metabolism.  Journal of Bacteriology.  185:7019-7023. 2003
    2003 Mycobacterial porins - New channel proteins in unique outer membranes 2003
    2003 High-level expression of the mycobacterial porin MspA in Escherichia coli and purification of the recombinant protein 2003
    2003 The core of the tetrameric mycobacterial porin MspA is an extremely stable β-sheet domain.  Journal of Biological Chemistry.  278:8678-8685. 2003
    2003 Purification of porins from Mycobacterium smegmatis..  Methods in Molecular Biology.  228:139-150. 2003
    2002 Nanostructuring by Deposition of Protein Channels Formed on Carbon Surfaces 2002
    2002 A tetrameric porin limits the cell wall permeability of Mycobacterium smegmatis.  Journal of Biological Chemistry.  277:37567-37572. 2002
    2001 Energy transfer between fluorescent proteins using a co-expression system in Mycobacterium smegmatis.  Gene.  278:115-124. 2001
    2001 Nanostructuring of Carbon Surfaces by Deposition of a Channel-Forming Protein and Subsequent Polymerization of Methyl Methacrylate Prepolymers 2001
    2001 Characterization of four members of a multigene family encoding outer membrane proteins of Helicobacter pylori and their potential for vaccination 2001
    2001 Modular organization of the AIDA autotransporter translocator: The N-terminal β1-domain is surface-exposed and stabilizes the transmembrane β2-domain 2001
    2001 MspA provides the main hydrophilic pathway through the cell wall of Mycobacterium smegmatis 2001
    2000 Selective extraction and purification of a mycobacterial outer membrane protein.  Analytical Biochemistry.  285:113-120. 2000
    2000 The FtsH protein accumulates at the septum of Bacillus subtilis during cell division and sporulation.  Journal of Bacteriology.  182:3870-3873. 2000
    2000 Quantitative analysis of gene expression with an improved green fluorescent protein 2000
    2000 Permeation of tetracyclines through membranes of liposomes and Escherichia coli 2000
    1999 Cloning of the mspA gene encoding a porin from Mycobacterium smegmatis 1999
    1999 Erratum: Porins in the cell wall of Mycobacterium tuberculosis (Journal of Bacteriology (1999) 181:20 (6543-6546)).  Journal of Bacteriology.  181:7650. 1999
    1999 Porins in the cell wall of Mycobacterium tuberculosis.  Journal of Bacteriology.  181:6543-6546. 1999
    1998 Biochemical and biophysical characterization of the cell wall porin of Corynebacterium glutamicum: The channel is formed by a low molecular mass polypeptide.  Biochemistry.  37:15024-15032. 1998
    1995 Identification of channel-forming activity in the cell wall of Corynebacterium glutamicum.  Journal of Bacteriology.  177:5716-5718. 1995
    1994 Oligo[d(C) · (G)] runs exhibit a helical repeat of 11.1 bp in solution and cause slight DNA curvature when properly phased.  Nucleic Acids Research.  22:1562-1566. 1994
    1994 Matrix effects suggest an important influence of DNA-polyacrylamide interactions on the electrophoretic mobility of DNA.  Journal of Biological Chemistry.  269:10156-10162. 1994
    1993 Synthesis of 8-Bromo- and 8-Azido-2’-Deoxyadenosine-5’-O-(1-Thiotriphosphate) 1993
    1993 Electrophoretic analysis of protein‐induced DNA bending and twist changes.  ELECTROPHORESIS.  14:693-698. 1993
    1992 An accurate method for determining the helical repeat of DNA in solution reveals differences to the crystal structures of two B-DNA decamers.  Journal of Molecular Biology.  228:322-326. 1992
    Stable Polymer Bilayers for Protein Channel Recordings at High Guanidinium Chloride Concentrations

    Chapter

    Year Title Altmetric
    2008 Experimental strategies toward the use of the porin MspA as a nanotemplate and for biosensors.  19-39. 2008
    Mycobacterial Porins.  153-165.

    Principal Investigator On

  • Heme and Hemoglobin Utilization by Mycobacterium Tuberculosis  awarded by National Institute of Allergy and Infectious Diseases/NIH/DHHS 2019 - 2023
  • Siderophore-Dependent Inhibitors of Mycobacterium Tuberculosis  awarded by National Institute of Allergy and Infectious Diseases/NIH/DHHS 2020 - 2022
  • The Necrosis-Inducing Toxin of Mycobacterium Tuberculosis  awarded by National Institute of Allergy and Infectious Diseases/NIH/DHHS 2015 - 2021
  • Single-chain MspA for Nanopore Sequencing of DNA  awarded by National Human Genome Research Institute/NIH/DHHS 2019 - 2021
  • Self-Poisoning of Mycobacterium Tuberculosis by Inhibiting Siderophore Secretion  awarded by TRES CANTOS OPEN LAB FOUNDATION 2016 - 2020
  • Killing and Sensitizing Bacterial Pathogens to Conventional Antibiotics Using a Protein Complex From Human Milk  awarded by UNIVERSITY OF LUND, SWEDEN 2015 - 2018
  • Nanopore Sequencing of DNA with MspA  awarded by UNIVERSITY OF WASHINGTON 2013 - 2017
  • M. Tuberculosis Membrane Protein Pharmaceutical Targets  awarded by Florida State University 2009 - 2015
  • Copper Transport in Mycobacterium Tuberculosis  awarded by National Institute of Allergy and Infectious Diseases/NIH/DHHS 2009 - 2015
  • Nanopore Sequencing of DNA with MspA  awarded by UNIVERSITY OF WASHINGTON 2009 - 2013
  • Characterization of a Mycobacterium Tuberculosis Porin with an Autotransporter-Like Toxin Activity  awarded by American Lung Association 2011 - 2012
  • The Interactions Network of the Outer Membrane Copper Efflux Channel Protein MctB of M. Tuberculosis  awarded by New York Community Trust 2009 - 2011

    • Investigator On

    Teaching Activities

  • GBS760 - Prokar Gene and Mole Bio (Spring Term 2018) 2018
  • GBSC720 - Journal Club 2 (Fall Term 2017) 2017
  • UNIV398 - Undergraduate Research (Fall Term 2017) 2017
  • GBS760 - Prokar Gene and Mole Bio (Spring Term 2017) 2017
  • GBSC720 - Journal Club 2 (Spring Term 2017) 2017
  • UNIV398 - Undergraduate Research (Spring Term 2017) 2017
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2016) 2016
  • UNIV398 - Undergraduate Research (Fall Term 2016) 2016
  • GBS760 - Prokar Gene and Mole Bio (Spring Term 2016) 2016
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2016) 2016
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2015) 2015
  • GBS760 - Prokar Gene and Mole Bio (Spring Term 2015) 2015
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2015) 2015
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2014) 2014
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2014) 2014
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2013) 2013
  • GBS760 - Prokar Gene and Mole Bio (Spring Term 2013) 2013
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2013) 2013
  • GBS708 - Basic Genetics/Mole BIo (Fall Term 2012) 2012
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2012) 2012
  • GBS708 - CORE COURSE II: GENETICS/MOLECULAR BIOLOGY (Fall Term 2012) 2012
  • GBS760 - Prokar Gene and Mole Bio (Spring Term 2012) 2012
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2012) 2012
  • GBS708 - Basic Genetics/Mole BIo (Fall Term 2011) 2011
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2011) 2011
  • GBS708 - CORE COURSE II: GENETICS/MOLECULAR BIOLOGY (Fall Term 2011) 2011
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2011) 2011
  • GBS708 - Basic Genetics/Mole BIo (Fall Term 2010) 2010
  • GBS760 - Prokar Gene and Mole Bio (Fall Term 2010) 2010
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2010) 2010
  • GBS708 - CORE COURSE II: GENETICS/MOLECULAR BIOLOGY (Fall Term 2010) 2010
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2010) 2010
  • CMB720 - CMB II Genes (Fall Term 2009) 2009
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2009) 2009
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2009) 2009
  • CMB720 - CMB II Genes (Fall Term 2008) 2008
  • MIC712 - Phys and Path of Mycobacteria (Fall Term 2008) 2008
  • MIC712 - Phys and Path of Mycobacteria (Spring Term 2008) 2008

    • Education And Training

  • Doctor of Philosophy in Microbiology, Friedrich-Alexander University of Erlangen-Nuremberg 1993

    • Full Name

  • Michael Niederweis