Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis

ABSTRACT A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex...

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Autores principales:	Jeffrey M. Flynn, Lydia C. Cameron, Talia D. Wiggen, Jordan M. Dunitz, William R. Harcombe, Ryan C. Hunter
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Pseudomonas aeruginosa antibiotics cross-feeding cystic fibrosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e1d0e59e56c340d5840da810d67defd0
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spelling	oai:doaj.org-article:e1d0e59e56c340d5840da810d67defd02021-11-15T15:29:17ZDisruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis10.1128/mSphere.00343-202379-5042https://doaj.org/article/e1d0e59e56c340d5840da810d67defd02020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00343-20https://doaj.org/toc/2379-5042ABSTRACT A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro. However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a “weakest-link” approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them. IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro, patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa. The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections.Jeffrey M. FlynnLydia C. CameronTalia D. WiggenJordan M. DunitzWilliam R. HarcombeRyan C. HunterAmerican Society for MicrobiologyarticlePseudomonas aeruginosaantibioticscross-feedingcystic fibrosisMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pseudomonas aeruginosa antibiotics cross-feeding cystic fibrosis Microbiology QR1-502
spellingShingle	Pseudomonas aeruginosa antibiotics cross-feeding cystic fibrosis Microbiology QR1-502 Jeffrey M. Flynn Lydia C. Cameron Talia D. Wiggen Jordan M. Dunitz William R. Harcombe Ryan C. Hunter Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis
description	ABSTRACT A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro. However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a “weakest-link” approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them. IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro, patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa. The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections.
format	article
author	Jeffrey M. Flynn Lydia C. Cameron Talia D. Wiggen Jordan M. Dunitz William R. Harcombe Ryan C. Hunter
author_facet	Jeffrey M. Flynn Lydia C. Cameron Talia D. Wiggen Jordan M. Dunitz William R. Harcombe Ryan C. Hunter
author_sort	Jeffrey M. Flynn
title	Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis
title_short	Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis
title_full	Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis
title_fullStr	Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis
title_full_unstemmed	Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis
title_sort	disruption of cross-feeding inhibits pathogen growth in the sputa of patients with cystic fibrosis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e1d0e59e56c340d5840da810d67defd0
work_keys_str_mv	AT jeffreymflynn disruptionofcrossfeedinginhibitspathogengrowthinthesputaofpatientswithcysticfibrosis AT lydiaccameron disruptionofcrossfeedinginhibitspathogengrowthinthesputaofpatientswithcysticfibrosis AT taliadwiggen disruptionofcrossfeedinginhibitspathogengrowthinthesputaofpatientswithcysticfibrosis AT jordanmdunitz disruptionofcrossfeedinginhibitspathogengrowthinthesputaofpatientswithcysticfibrosis AT williamrharcombe disruptionofcrossfeedinginhibitspathogengrowthinthesputaofpatientswithcysticfibrosis AT ryanchunter disruptionofcrossfeedinginhibitspathogengrowthinthesputaofpatientswithcysticfibrosis
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Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis

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