Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>

ABSTRACT Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide e...

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Autores principales:	Sarah E. Greene, Jerome S. Pinkner, Erik Chorell, Karen W. Dodson, Carrie L. Shaffer, Matt S. Conover, Jonathan Livny, Maria Hadjifrangiskou, Fredrik Almqvist, Scott J. Hultgren
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4870dddc644f4c4fb9421e07a3921141
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spelling	oai:doaj.org-article:4870dddc644f4c4fb9421e07a39211412021-11-15T15:47:03ZPilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>10.1128/mBio.02038-142150-7511https://doaj.org/article/4870dddc644f4c4fb9421e07a39211412014-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02038-14https://doaj.org/toc/2150-7511ABSTRACT Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240’s inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.Sarah E. GreeneJerome S. PinknerErik ChorellKaren W. DodsonCarrie L. ShafferMatt S. ConoverJonathan LivnyMaria HadjifrangiskouFredrik AlmqvistScott J. HultgrenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 6 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Sarah E. Greene Jerome S. Pinkner Erik Chorell Karen W. Dodson Carrie L. Shaffer Matt S. Conover Jonathan Livny Maria Hadjifrangiskou Fredrik Almqvist Scott J. Hultgren Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>
description	ABSTRACT Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240’s inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.
format	article
author	Sarah E. Greene Jerome S. Pinkner Erik Chorell Karen W. Dodson Carrie L. Shaffer Matt S. Conover Jonathan Livny Maria Hadjifrangiskou Fredrik Almqvist Scott J. Hultgren
author_facet	Sarah E. Greene Jerome S. Pinkner Erik Chorell Karen W. Dodson Carrie L. Shaffer Matt S. Conover Jonathan Livny Maria Hadjifrangiskou Fredrik Almqvist Scott J. Hultgren
author_sort	Sarah E. Greene
title	Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_short	Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_full	Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_fullStr	Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_full_unstemmed	Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>
title_sort	pilicide ec240 disrupts virulence circuits in uropathogenic <named-content content-type="genus-species">escherichia coli</named-content>
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/4870dddc644f4c4fb9421e07a3921141
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Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic <named-content content-type="genus-species">Escherichia coli</named-content>

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