<italic toggle="yes">Salmonella</italic> 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2016-09-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01238-16 |
| _version_ | 1819203085257408512 |
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| author | Joris van der Heijden Lisa A. Reynolds Wanyin Deng Allan Mills Roland Scholz Koshi Imami Leonard J. Foster Franck Duong B. Brett Finlay |
| author_facet | Joris van der Heijden Lisa A. Reynolds Wanyin Deng Allan Mills Roland Scholz Koshi Imami Leonard J. Foster Franck Duong B. Brett Finlay |
| author_sort | Joris van der Heijden |
| collection | DOAJ |
| description | 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. IMPORTANCE 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. |
| first_indexed | 2024-12-23T04:14:18Z |
| format | Article |
| id | doaj.art-4b0a81694cef451481ba9db78777355b |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-23T04:14:18Z |
| publishDate | 2016-09-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-4b0a81694cef451481ba9db78777355b2022-12-21T18:00:24ZengAmerican Society for MicrobiologymBio2150-75112016-09-017410.1128/mBio.01238-16<italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative StressJoris van der Heijden0Lisa A. Reynolds1Wanyin Deng2Allan Mills3Roland Scholz4Koshi Imami5Leonard J. Foster6Franck Duong7B. Brett Finlay8Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, CanadaDepartment of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, CanadaCenter for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, CanadaCenter for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, CanadaDepartment of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, CanadaMichael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, CanadaABSTRACT 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. IMPORTANCE 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.https://journals.asm.org/doi/10.1128/mBio.01238-16 |
| spellingShingle | Joris van der Heijden Lisa A. Reynolds Wanyin Deng Allan Mills Roland Scholz Koshi Imami Leonard J. Foster Franck Duong B. Brett Finlay <italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative Stress mBio |
| title | <italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative Stress |
| title_full | <italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative Stress |
| title_fullStr | <italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative Stress |
| title_full_unstemmed | <italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative Stress |
| title_short | <italic toggle="yes">Salmonella</italic> Rapidly Regulates Membrane Permeability To Survive Oxidative Stress |
| title_sort | italic toggle yes salmonella italic rapidly regulates membrane permeability to survive oxidative stress |
| url | https://journals.asm.org/doi/10.1128/mBio.01238-16 |
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