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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Autores principales:	Omar M. El-Halfawy, Javier Klett, Rebecca J. Ingram, Slade A. Loutet, Michael E. P. Murphy, Sonsoles Martín-Santamaría, Miguel A. Valvano
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/26004c45d3264251a4055de0fd997b9b
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spelling	oai:doaj.org-article:26004c45d3264251a4055de0fd997b9b2021-11-15T15:51:00ZAntibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance10.1128/mBio.00225-172150-7511https://doaj.org/article/26004c45d3264251a4055de0fd997b9b2017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00225-17https://doaj.org/toc/2150-7511ABSTRACT 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.Omar M. El-HalfawyJavier KlettRebecca J. IngramSlade A. LoutetMichael E. P. MurphySonsoles Martín-SantamaríaMiguel A. ValvanoAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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
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.
format	article
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
title	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_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_sort	antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/26004c45d3264251a4055de0fd997b9b
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Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance

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