<i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence

Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence o...
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Autor*in:	Mylene Vaillancourt [verfasserIn] Sam P. Limsuwannarot [verfasserIn] Catherine Bresee [verfasserIn] Rahgavi Poopalarajah [verfasserIn] Peter Jorth [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	efflux pumps virulence evolution antibiotic resistance cystic fibrosis

Übergeordnetes Werk:	In: Antibiotics - MDPI AG, 2013, 10(2021), 10, p 1164
Übergeordnetes Werk:	volume:10 ; year:2021 ; number:10, p 1164

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/antibiotics10101164

Katalog-ID:	DOAJ054393647

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520			\|a Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.
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650		4	\|a efflux pumps
650		4	\|a virulence
650		4	\|a evolution
650		4	\|a antibiotic resistance
650		4	\|a cystic fibrosis
653		0	\|a Therapeutics. Pharmacology
700	0		\|a Sam P. Limsuwannarot \|e verfasserin \|4 aut
700	0		\|a Catherine Bresee \|e verfasserin \|4 aut
700	0		\|a Rahgavi Poopalarajah \|e verfasserin \|4 aut
700	0		\|a Peter Jorth \|e verfasserin \|4 aut
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912			\|a GBV_ILN_213
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allfields	10.3390/antibiotics10101164 doi (DE-627)DOAJ054393647 (DE-599)DOAJ9ff32987f2ec4cb9a833b7485145f355 DE-627 ger DE-627 rakwb eng RM1-950 Mylene Vaillancourt verfasserin aut <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution. <i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis Therapeutics. Pharmacology Sam P. Limsuwannarot verfasserin aut Catherine Bresee verfasserin aut Rahgavi Poopalarajah verfasserin aut Peter Jorth verfasserin aut In Antibiotics MDPI AG, 2013 10(2021), 10, p 1164 (DE-627)726120596 (DE-600)2681345-2 20796382 nnns volume:10 year:2021 number:10, p 1164 https://doi.org/10.3390/antibiotics10101164 kostenfrei https://doaj.org/article/9ff32987f2ec4cb9a833b7485145f355 kostenfrei https://www.mdpi.com/2079-6382/10/10/1164 kostenfrei https://doaj.org/toc/2079-6382 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 10, p 1164
spelling	10.3390/antibiotics10101164 doi (DE-627)DOAJ054393647 (DE-599)DOAJ9ff32987f2ec4cb9a833b7485145f355 DE-627 ger DE-627 rakwb eng RM1-950 Mylene Vaillancourt verfasserin aut <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution. <i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis Therapeutics. Pharmacology Sam P. Limsuwannarot verfasserin aut Catherine Bresee verfasserin aut Rahgavi Poopalarajah verfasserin aut Peter Jorth verfasserin aut In Antibiotics MDPI AG, 2013 10(2021), 10, p 1164 (DE-627)726120596 (DE-600)2681345-2 20796382 nnns volume:10 year:2021 number:10, p 1164 https://doi.org/10.3390/antibiotics10101164 kostenfrei https://doaj.org/article/9ff32987f2ec4cb9a833b7485145f355 kostenfrei https://www.mdpi.com/2079-6382/10/10/1164 kostenfrei https://doaj.org/toc/2079-6382 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 10, p 1164
allfields_unstemmed	10.3390/antibiotics10101164 doi (DE-627)DOAJ054393647 (DE-599)DOAJ9ff32987f2ec4cb9a833b7485145f355 DE-627 ger DE-627 rakwb eng RM1-950 Mylene Vaillancourt verfasserin aut <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution. <i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis Therapeutics. Pharmacology Sam P. Limsuwannarot verfasserin aut Catherine Bresee verfasserin aut Rahgavi Poopalarajah verfasserin aut Peter Jorth verfasserin aut In Antibiotics MDPI AG, 2013 10(2021), 10, p 1164 (DE-627)726120596 (DE-600)2681345-2 20796382 nnns volume:10 year:2021 number:10, p 1164 https://doi.org/10.3390/antibiotics10101164 kostenfrei https://doaj.org/article/9ff32987f2ec4cb9a833b7485145f355 kostenfrei https://www.mdpi.com/2079-6382/10/10/1164 kostenfrei https://doaj.org/toc/2079-6382 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 10, p 1164
allfieldsGer	10.3390/antibiotics10101164 doi (DE-627)DOAJ054393647 (DE-599)DOAJ9ff32987f2ec4cb9a833b7485145f355 DE-627 ger DE-627 rakwb eng RM1-950 Mylene Vaillancourt verfasserin aut <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution. <i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis Therapeutics. Pharmacology Sam P. Limsuwannarot verfasserin aut Catherine Bresee verfasserin aut Rahgavi Poopalarajah verfasserin aut Peter Jorth verfasserin aut In Antibiotics MDPI AG, 2013 10(2021), 10, p 1164 (DE-627)726120596 (DE-600)2681345-2 20796382 nnns volume:10 year:2021 number:10, p 1164 https://doi.org/10.3390/antibiotics10101164 kostenfrei https://doaj.org/article/9ff32987f2ec4cb9a833b7485145f355 kostenfrei https://www.mdpi.com/2079-6382/10/10/1164 kostenfrei https://doaj.org/toc/2079-6382 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 10, p 1164
allfieldsSound	10.3390/antibiotics10101164 doi (DE-627)DOAJ054393647 (DE-599)DOAJ9ff32987f2ec4cb9a833b7485145f355 DE-627 ger DE-627 rakwb eng RM1-950 Mylene Vaillancourt verfasserin aut <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution. <i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis Therapeutics. Pharmacology Sam P. Limsuwannarot verfasserin aut Catherine Bresee verfasserin aut Rahgavi Poopalarajah verfasserin aut Peter Jorth verfasserin aut In Antibiotics MDPI AG, 2013 10(2021), 10, p 1164 (DE-627)726120596 (DE-600)2681345-2 20796382 nnns volume:10 year:2021 number:10, p 1164 https://doi.org/10.3390/antibiotics10101164 kostenfrei https://doaj.org/article/9ff32987f2ec4cb9a833b7485145f355 kostenfrei https://www.mdpi.com/2079-6382/10/10/1164 kostenfrei https://doaj.org/toc/2079-6382 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 10, p 1164
language	English
source	In Antibiotics 10(2021), 10, p 1164 volume:10 year:2021 number:10, p 1164
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topic_facet	<i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis Therapeutics. Pharmacology
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authorswithroles_txt_mv	Mylene Vaillancourt @@aut@@ Sam P. Limsuwannarot @@aut@@ Catherine Bresee @@aut@@ Rahgavi Poopalarajah @@aut@@ Peter Jorth @@aut@@
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callnumber-first	R - Medicine
author	Mylene Vaillancourt
spellingShingle	Mylene Vaillancourt misc RM1-950 misc <i<Pseudomonas</i< misc efflux pumps misc virulence misc evolution misc antibiotic resistance misc cystic fibrosis misc Therapeutics. Pharmacology <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence
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topic_title	RM1-950 <i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence <i<Pseudomonas</i< efflux pumps virulence evolution antibiotic resistance cystic fibrosis
topic	misc RM1-950 misc <i<Pseudomonas</i< misc efflux pumps misc virulence misc evolution misc antibiotic resistance misc cystic fibrosis misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc <i<Pseudomonas</i< misc efflux pumps misc virulence misc evolution misc antibiotic resistance misc cystic fibrosis misc Therapeutics. Pharmacology
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title	<i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence
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title_sort	<i<pseudomonas aeruginosa</i< <i<mexr</i< and <i<mexef</i< antibiotic efflux pump variants exhibit increased virulence
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title_auth	<i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence
abstract	Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.
abstractGer	Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.
abstract_unstemmed	Antibiotic-resistant <i<Pseudomonas aeruginosa</i< infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase <i<P. aeruginosa</i< virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase <i<P. aeruginosa</i< virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the <i<mexEF</i< efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in <i<mexR</i< that increased expression of the <i<mexAB-oprM</i< efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for <i<P. aeruginosa</i<, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.
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title_short	<i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence
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<i<Pseudomonas aeruginosa</i< <i<mexR</i< and <i<mexEF</i< Antibiotic Efflux Pump Variants Exhibit Increased Virulence

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