H2S: A Universal Defense Against Antibiotics in Bacteria

Sulfide formation helps to protect various bacteria from antibiotic toxicity. Many prokaryotic species generate hydrogen sulfide (H2S) in their natural environments. However, the biochemistry and physiological role of this gas in nonsulfur bacteria remain largely unknown. Here we demonstrate that inactivation of putative cystathionine β-synthase, cystathionine γ-lyase, or 3-mercaptopyruvate sulfurtransferase in Bacillus anthracis, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli suppresses H2S production, rendering these pathogens highly sensitive to a multitude of antibiotics. Exogenous H2S suppresses this effect. Moreover, in bacteria that normally produce H2S and nitric oxide, these two gases act synergistically to sustain growth. The mechanism of gas-mediated antibiotic resistance relies on mitigation of oxidative stress imposed by antibiotics.

[1]  E. Kolaczyk,et al.  Wolbachia Enhance Drosophila Stem Cell Proliferation and Target the Germline Stem Cell Niche , 2011, Science.

[2]  J. Collins,et al.  How antibiotics kill bacteria: from targets to networks , 2010, Nature Reviews Microbiology.

[3]  Rui Wang,et al.  Hydrogen sulfide: the third gasotransmitter in biology and medicine. , 2010, Antioxidants & redox signaling.

[4]  H. Kimura.  Hydrogen sulfide: from brain to gut. , 2010, Antioxidants & redox signaling.

[5]  S. Snyder,et al.  Hydrogen sulfide as a gasotransmitter , 2010, Journal of neurochemistry.

[6]  J. Stamler,et al.  S-Nitrosylation in Cardiovascular Signaling , 2010, Circulation research.

[7]  J. Collins,et al.  Hydroxyurea induces hydroxyl radical-mediated cell death in Escherichia coli. , 2009, Molecular cell.

[8]  E. Nudler,et al.  Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics , 2009, Science.

[9]  S. Snyder,et al.  Signaling by Gasotransmitters , 2009, Science Signaling.

[10]  G. Anand,et al.  Structural Basis for the Inhibition Mechanism of Human Cystathionine γ-Lyase, an Enzyme Responsible for the Production of H2S* , 2009, Journal of Biological Chemistry.

[11]  S. Lippard,et al.  Bacterial Nitric-oxide Synthases Operate without a Dedicated Redox Partner* , 2008, Journal of Biological Chemistry.

[12]  S. Lippard,et al.  Bacillus anthracis-derived nitric oxide is essential for pathogen virulence and survival in macrophages , 2008, Proceedings of the National Academy of Sciences.

[13]  J. Collins,et al.  A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics , 2007, Cell.

[14]  S. Lippard,et al.  Visualization of nitric oxide in living cells by a copper-based fluorescent probe , 2006, Nature chemical biology.

[15]  I. Dunham,et al.  The DNA sequence and biological annotation of human chromosome 1 , 2006, Nature.

[16]  P. Hanna,et al.  Characterization of Bacillus anthracis Germinant Receptors In Vitro , 2005, Journal of bacteriology.

[17]  E. Nudler,et al.  NO-mediated cytoprotection: instant adaptation to oxidative stress in bacteria. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Mashko,et al.  [Tuning of expression level of the genes of interest located in the bacterial chromosome]. , 2005, Molekuliarnaia biologiia.

[19]  H. Mori,et al.  Identification and Functional Analysis of Escherichia coli Cysteine Desulfhydrases , 2005, Applied and Environmental Microbiology.

[20]  Konstantin Shatalin,et al.  Efficient gene inactivation in Bacillus anthracis. , 2005, FEMS microbiology letters.

[21]  J. Imlay,et al.  Pathways of oxidative damage. , 2003, Annual review of microbiology.

[22]  J. Imlay,et al.  High Levels of Intracellular Cysteine Promote Oxidative DNA Damage by Driving the Fenton Reaction , 2003, Journal of bacteriology.

[23]  G. Rubin,et al.  Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Jack T Trevors,et al.  Green fluorescent protein-based biosensor for detecting SOS-inducing activity of genotoxic compounds. , 2002, Journal of microbiological methods.

[25]  P Burkhard,et al.  Structure of human cystathionine β‐synthase: a unique pyridoxal 5′‐phosphate‐dependent heme protein , 2001, The EMBO journal.

[26]  B. Wanner,et al.  One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Melanie E. Goward,et al.  The DNA sequence of human chromosome 22 , 1999, Nature.

[28]  I. Fridovich,et al.  Superoxide and Iron: Partners in Crime , 1999, IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology.

[29]  H. Bujard,et al.  Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. , 1997, Nucleic acids research.

[30]  J. Helmann,et al.  Coordinate regulation of Bacillus subtilis peroxide stress genes by hydrogen peroxide and metal ions. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Bruce W. Birren,et al.  Pulsed field gel electrophoresis. A practical guide. , 1993 .

[32]  Á. Leitão,et al.  Effects of metal ion chelators on DNA strand breaks and inactivation produced by hydrogen peroxide in Escherichia coli: detection of iron-independent lesions , 1991, Journal of bacteriology.

[33]  O. Aruoma,et al.  Damage to the bases in DNA induced by hydrogen peroxide and ferric ion chelates. , 1989, The Journal of biological chemistry.