Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance
ABSTRACT The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2017-05-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00225-17 |
| _version_ | 1818434535463845888 |
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| author | Omar M. El-Halfawy Javier Klett Rebecca J. Ingram Slade A. Loutet Michael E. P. Murphy Sonsoles Martín-Santamaría Miguel A. Valvano |
| author_facet | Omar M. El-Halfawy Javier Klett Rebecca J. Ingram Slade A. Loutet Michael E. P. Murphy Sonsoles Martín-Santamaría Miguel A. Valvano |
| author_sort | Omar M. El-Halfawy |
| collection | DOAJ |
| description | ABSTRACT The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins. IMPORTANCE Current research on antibiotic action and resistance focuses on targeting essential functions within bacterial cells. We discovered a previously unrecognized mode of general bacterial antibiotic resistance operating in the extracellular space, which depends on bacterial protein molecules called lipocalins. These molecules are highly conserved in most bacteria and have the ability to capture different classes of antibiotics outside bacterial cells. We also discovered that liposoluble vitamins, such as vitamin E, overcome in vitro and in vivo antibiotic resistance mediated by bacterial lipocalins, providing an unexpected new alternative to combat resistance by using this vitamin or its derivatives as antibiotic adjuvants. |
| first_indexed | 2024-12-14T16:38:32Z |
| format | Article |
| id | doaj.art-26004c45d3264251a4055de0fd997b9b |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T16:38:32Z |
| publishDate | 2017-05-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-26004c45d3264251a4055de0fd997b9b2022-12-21T22:54:23ZengAmerican Society for MicrobiologymBio2150-75112017-05-018210.1128/mBio.00225-17Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic ResistanceOmar M. El-Halfawy0Javier Klett1Rebecca J. Ingram2Slade A. Loutet3Michael E. P. Murphy4Sonsoles Martín-Santamaría5Miguel A. Valvano6Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, CanadaDepartment of Chemical and Physical Biology, Centre for Biological Research, CIB, CSIC, Madrid, SpainThe Wellcome-Wolfson Institute of Experimental Medicine, Queen’s University Belfast, Belfast, United KingdomDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, CanadaDepartment of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, CanadaDepartment of Chemical and Physical Biology, Centre for Biological Research, CIB, CSIC, Madrid, SpainDepartment of Microbiology and Immunology, University of Western Ontario, London, Ontario, CanadaABSTRACT The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins. IMPORTANCE Current research on antibiotic action and resistance focuses on targeting essential functions within bacterial cells. We discovered a previously unrecognized mode of general bacterial antibiotic resistance operating in the extracellular space, which depends on bacterial protein molecules called lipocalins. These molecules are highly conserved in most bacteria and have the ability to capture different classes of antibiotics outside bacterial cells. We also discovered that liposoluble vitamins, such as vitamin E, overcome in vitro and in vivo antibiotic resistance mediated by bacterial lipocalins, providing an unexpected new alternative to combat resistance by using this vitamin or its derivatives as antibiotic adjuvants.https://journals.asm.org/doi/10.1128/mBio.00225-17 |
| spellingShingle | Omar M. El-Halfawy Javier Klett Rebecca J. Ingram Slade A. Loutet Michael E. P. Murphy Sonsoles Martín-Santamaría Miguel A. Valvano Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance mBio |
| title | Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance |
| title_full | Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance |
| title_fullStr | Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance |
| title_full_unstemmed | Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance |
| title_short | Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance |
| title_sort | antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance |
| url | https://journals.asm.org/doi/10.1128/mBio.00225-17 |
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