An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds

ABSTRACT The antibiotic paenimucillin A was originally identified using a culture-independent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Here we report on a bioinformatics-guided survey of paenimucillin A analogs that led to the discovery of paenimucillin C. Paenimucillin...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xavier Vila-Farres, John Chu, Melinda A. Ternei, Christophe Lemetre, Steven Park, David S. Perlin, Sean F. Brady
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Acinetobacter baumannii antibiotics syn-BNP wound infections Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2fae744c0e1e459fa175a0b1daaaf57e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2fae744c0e1e459fa175a0b1daaaf57e
record_format	dspace
spelling	oai:doaj.org-article:2fae744c0e1e459fa175a0b1daaaf57e2021-11-15T15:22:01ZAn Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds10.1128/mSphere.00528-172379-5042https://doaj.org/article/2fae744c0e1e459fa175a0b1daaaf57e2018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00528-17https://doaj.org/toc/2379-5042ABSTRACT The antibiotic paenimucillin A was originally identified using a culture-independent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Here we report on a bioinformatics-guided survey of paenimucillin A analogs that led to the discovery of paenimucillin C. Paenimucillin C inhibits the growth of multidrug-resistant (MDR) Acinetobacter baumannii clinical isolates, as well as other Gram-negative bacterial pathogens. In a rat cutaneous wound model, it completely sterilized MDR A. baumannii wound infections with no sign of rebound. Mechanistic studies point to a membrane-associated mode of action that results in leakage of intracellular contents. IMPORTANCE Natural product-inspired antibiotics have saved millions of lives and played a critical role in modern medicine. However, the emergence of drug-resistant pathogens is outpacing the rate at which new clinically useful antibiotics are being discovered. The lack of a means to combat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii is of particular concern. The sharp increase in cases of MDR A. baumannii infections in recent years prompted the CDC (https://www.cdc.gov/drugresistance/biggest_threats.html) and WHO (http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/) to list this pathogen as a “serious threat” and “critical pathogen,” respectively. Here we report a new antibiotic, paenimucillin C, active against Gram-negative bacterial pathogens, including many clinical isolates of MDR A. baumannii strains. Mechanistic studies point to membrane disruption leading to leakage of intracellular contents as its antibacterial mode of action. Paenimucillin C sterilizes MDR A. baumannii infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen.Xavier Vila-FarresJohn ChuMelinda A. TerneiChristophe LemetreSteven ParkDavid S. PerlinSean F. BradyAmerican Society for MicrobiologyarticleAcinetobacter baumanniiantibioticssyn-BNPwound infectionsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter baumannii antibiotics syn-BNP wound infections Microbiology QR1-502
spellingShingle	Acinetobacter baumannii antibiotics syn-BNP wound infections Microbiology QR1-502 Xavier Vila-Farres John Chu Melinda A. Ternei Christophe Lemetre Steven Park David S. Perlin Sean F. Brady An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds
description	ABSTRACT The antibiotic paenimucillin A was originally identified using a culture-independent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Here we report on a bioinformatics-guided survey of paenimucillin A analogs that led to the discovery of paenimucillin C. Paenimucillin C inhibits the growth of multidrug-resistant (MDR) Acinetobacter baumannii clinical isolates, as well as other Gram-negative bacterial pathogens. In a rat cutaneous wound model, it completely sterilized MDR A. baumannii wound infections with no sign of rebound. Mechanistic studies point to a membrane-associated mode of action that results in leakage of intracellular contents. IMPORTANCE Natural product-inspired antibiotics have saved millions of lives and played a critical role in modern medicine. However, the emergence of drug-resistant pathogens is outpacing the rate at which new clinically useful antibiotics are being discovered. The lack of a means to combat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii is of particular concern. The sharp increase in cases of MDR A. baumannii infections in recent years prompted the CDC (https://www.cdc.gov/drugresistance/biggest_threats.html) and WHO (http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/) to list this pathogen as a “serious threat” and “critical pathogen,” respectively. Here we report a new antibiotic, paenimucillin C, active against Gram-negative bacterial pathogens, including many clinical isolates of MDR A. baumannii strains. Mechanistic studies point to membrane disruption leading to leakage of intracellular contents as its antibacterial mode of action. Paenimucillin C sterilizes MDR A. baumannii infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen.
format	article
author	Xavier Vila-Farres John Chu Melinda A. Ternei Christophe Lemetre Steven Park David S. Perlin Sean F. Brady
author_facet	Xavier Vila-Farres John Chu Melinda A. Ternei Christophe Lemetre Steven Park David S. Perlin Sean F. Brady
author_sort	Xavier Vila-Farres
title	An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds
title_short	An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds
title_full	An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds
title_fullStr	An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds
title_full_unstemmed	An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds
title_sort	optimized synthetic-bioinformatic natural product antibiotic sterilizes multidrug-resistant <named-content content-type="genus-species">acinetobacter baumannii</named-content>-infected wounds
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/2fae744c0e1e459fa175a0b1daaaf57e
work_keys_str_mv	AT xaviervilafarres anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT johnchu anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT melindaaternei anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT christophelemetre anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT stevenpark anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT davidsperlin anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT seanfbrady anoptimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT xaviervilafarres optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT johnchu optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT melindaaternei optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT christophelemetre optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT stevenpark optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT davidsperlin optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds AT seanfbrady optimizedsyntheticbioinformaticnaturalproductantibioticsterilizesmultidrugresistantnamedcontentcontenttypegenusspeciesacinetobacterbaumanniinamedcontentinfectedwounds
_version_	1718428062126702592

An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content>-Infected Wounds

Ejemplares similares