title: Salmonella Rapidly Regulates Membrane Permeability To Survive Oxidative Stress.
abstract: The outer membrane (OM) of Gram-negative bacteria provides protection against toxic molecules, including reactive oxygen species (ROS). Decreased OM permeability can promote bacterial survival under harsh circumstances and protects against antibiotics. To better understand the regulation of OM permeability, we studied the real-time influx of hydrogen peroxide in Salmonella bacteria and discovered two novel mechanisms by which they rapidly control OM permeability. We found that pores in two major OM proteins, OmpA and OmpC, could be rapidly opened or closed when oxidative stress is encountered and that the underlying mechanisms rely on the formation of disulfide bonds in the periplasmic domain of OmpA and TrxA, respectively. Additionally, we found that a Salmonella mutant showing increased OM permeability was killed more effectively by treatment with antibiotics. Together, these results demonstrate that Gram-negative bacteria regulate the influx of ROS for defense against oxidative stress and reveal novel targets that can be therapeutically targeted to increase bacterial killing by conventional antibiotics.
  
  
  
  Pathogenic bacteria have evolved ways to circumvent inflammatory immune responses. A decrease in bacterial outer membrane permeability during infection helps protect bacteria from toxic molecules produced by the host immune system and allows for effective colonization of the host. In this report, we reveal molecular mechanisms that rapidly alter outer membrane pores and their permeability in response to hydrogen peroxide and oxidative stress. These mechanisms are the first examples of pores that are rapidly opened or closed in response to reactive oxygen species. Moreover, one of these mechanisms can be targeted to artificially increase membrane permeability and thereby increase bacterial killing by the antibiotic cefotaxime during in vitro experiments and in a mouse model of infection. We envision that a better understanding of the regulation of membrane permeability will lead to new targets and treatment options for multidrug-resistant infections.
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Joris
authors: J
authors: van der Heijden
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Lisa A
authors: LA
authors: Reynolds
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Wanyin
authors: W
authors: Deng
authors: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Allan
authors: A
authors: Mills
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Roland
authors: R
authors: Scholz
authors: Center for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Koshi
authors: K
authors: Imami
authors: Center for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Leonard J
authors: LJ
authors: Foster
authors: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Franck
authors: F
authors: Duong
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada bfinlay@interchange.ubc.ca.
authors: B Brett
authors: BB
authors: Finlay
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D058491:Bacterial Load; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000633:toxicity; D008566:Membranes / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010539:Permeability; D018272:Porins / Q000737:chemistry / Q000378:metabolism; D012475:Salmonella / Q000502:physiology*; D012481:Salmonella Infections, Animal / Q000382:microbiology; D013312:Stress, Physiological
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; C113724:OmpC protein; D018272:Porins; C078167:OMPA outer membrane proteins; D006861:Hydrogen Peroxide