The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

ABSTRACT Biofilm-forming bacteria, including the Gram-negative Pseudomonas aeruginosa, cause multiple types of chronic infections and are responsible for serious health burdens in humans, animals, and plants. Nitric oxide (NO) has been shown to induce biofilm dispersal via triggering a reduction in...

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Autores principales:	Ji-Su Park, Ha-Young Choi, Won-Gon Kim
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	biofilms Pseudomonas aeruginosa nitric oxide nitrite transporter drug target Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8f20a6a7385d4ca2bdbcbbcb412a5781
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spelling	oai:doaj.org-article:8f20a6a7385d4ca2bdbcbbcb412a57812021-11-15T15:56:43ZThe Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>10.1128/mBio.00878-202150-7511https://doaj.org/article/8f20a6a7385d4ca2bdbcbbcb412a57812020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00878-20https://doaj.org/toc/2150-7511ABSTRACT Biofilm-forming bacteria, including the Gram-negative Pseudomonas aeruginosa, cause multiple types of chronic infections and are responsible for serious health burdens in humans, animals, and plants. Nitric oxide (NO) has been shown to induce biofilm dispersal via triggering a reduction in cyclic-di-GMP levels in a variety of bacteria. However, how NO, at homeostatic levels, also facilitates biofilm formation is unknown. Here, we found that complestatin, a structural analog of vancomycin isolated from Streptomyces, inhibits P. aeruginosa biofilm formation by upregulating NO production via nitrite reductase (NIR) induction and c-di-GMP degradation via phosphodiesterase (PDE) stimulation. The complestatin protein target was identified as a nitrite transporter from a genome-wide screen using the Keio Escherichia coli knockout library and confirmed using nitrite transporter knockout and overexpression strains. We demonstrated that the nitrite transporter stimulated biofilm formation by controlled NO production via appropriate NIR suppression and subsequent diguanylate cyclase (DGC) activation, not PDE activity, and c-di-GMP production in E. coli and P. aeruginosa. Thus, this study provides a mechanism for NO-mediated biofilm formation, which was previously not understood. IMPORTANCE Bacterial biofilms play roles in infections and avoidance of host defense mechanisms of medically important pathogens and increase the antibiotic resistance of the bacteria. Nitric oxide (NO) is reported to be involved in both biofilm formation and dispersal, which are conflicting processes. The mechanism by which NO regulates biofilm dispersal is relatively understood, but there are no reports about how NO is involved in biofilm formation. Here, by investigating the mechanism by which complestatin inhibits biofilm formation, we describe a novel mechanism for governing biofilm formation in Escherichia coli and Pseudomonas aeruginosa. Nitrite transporter is required for biofilm formation via regulation of NO levels and subsequent c-di-GMP production. Additionally, the nitrite transporter contributes more to P. aeruginosa virulence than quorum sensing. Thus, this study identifies nitrite transporters as new antibiofilm targets for future practical and therapeutic agent development.Ji-Su ParkHa-Young ChoiWon-Gon KimAmerican Society for MicrobiologyarticlebiofilmsPseudomonas aeruginosanitric oxidenitrite transporterdrug targetMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	biofilms Pseudomonas aeruginosa nitric oxide nitrite transporter drug target Microbiology QR1-502
spellingShingle	biofilms Pseudomonas aeruginosa nitric oxide nitrite transporter drug target Microbiology QR1-502 Ji-Su Park Ha-Young Choi Won-Gon Kim The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
description	ABSTRACT Biofilm-forming bacteria, including the Gram-negative Pseudomonas aeruginosa, cause multiple types of chronic infections and are responsible for serious health burdens in humans, animals, and plants. Nitric oxide (NO) has been shown to induce biofilm dispersal via triggering a reduction in cyclic-di-GMP levels in a variety of bacteria. However, how NO, at homeostatic levels, also facilitates biofilm formation is unknown. Here, we found that complestatin, a structural analog of vancomycin isolated from Streptomyces, inhibits P. aeruginosa biofilm formation by upregulating NO production via nitrite reductase (NIR) induction and c-di-GMP degradation via phosphodiesterase (PDE) stimulation. The complestatin protein target was identified as a nitrite transporter from a genome-wide screen using the Keio Escherichia coli knockout library and confirmed using nitrite transporter knockout and overexpression strains. We demonstrated that the nitrite transporter stimulated biofilm formation by controlled NO production via appropriate NIR suppression and subsequent diguanylate cyclase (DGC) activation, not PDE activity, and c-di-GMP production in E. coli and P. aeruginosa. Thus, this study provides a mechanism for NO-mediated biofilm formation, which was previously not understood. IMPORTANCE Bacterial biofilms play roles in infections and avoidance of host defense mechanisms of medically important pathogens and increase the antibiotic resistance of the bacteria. Nitric oxide (NO) is reported to be involved in both biofilm formation and dispersal, which are conflicting processes. The mechanism by which NO regulates biofilm dispersal is relatively understood, but there are no reports about how NO is involved in biofilm formation. Here, by investigating the mechanism by which complestatin inhibits biofilm formation, we describe a novel mechanism for governing biofilm formation in Escherichia coli and Pseudomonas aeruginosa. Nitrite transporter is required for biofilm formation via regulation of NO levels and subsequent c-di-GMP production. Additionally, the nitrite transporter contributes more to P. aeruginosa virulence than quorum sensing. Thus, this study identifies nitrite transporters as new antibiofilm targets for future practical and therapeutic agent development.
format	article
author	Ji-Su Park Ha-Young Choi Won-Gon Kim
author_facet	Ji-Su Park Ha-Young Choi Won-Gon Kim
author_sort	Ji-Su Park
title	The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_short	The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full	The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_fullStr	The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full_unstemmed	The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_sort	nitrite transporter facilitates biofilm formation via suppression of nitrite reductase and is a new antibiofilm target in <named-content content-type="genus-species">pseudomonas aeruginosa</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8f20a6a7385d4ca2bdbcbbcb412a5781
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The Nitrite Transporter Facilitates Biofilm Formation via Suppression of Nitrite Reductase and Is a New Antibiofilm Target in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

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