Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps

ABSTRACT It is generally assumed that the acquisition of antibiotic resistance is associated with a fitness cost. We have shown that overexpression of the MexEF-OprN efflux pump does not decrease the fitness of a resistant Pseudomonas aeruginosa strain compared to its wild-type counterpart. This lac...

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Autores principales:	Jorge Olivares Pacheco, Carolina Alvarez-Ortega, Manuel Alcalde Rico, José Luis Martínez
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Pseudomonas aeruginosa antibiotic resistance efflux pumps fitness costs Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/81c0d553a1c8444da725d9b2574b3ab4
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spelling	oai:doaj.org-article:81c0d553a1c8444da725d9b2574b3ab42021-11-15T15:51:42ZMetabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps10.1128/mBio.00500-172150-7511https://doaj.org/article/81c0d553a1c8444da725d9b2574b3ab42017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00500-17https://doaj.org/toc/2150-7511ABSTRACT It is generally assumed that the acquisition of antibiotic resistance is associated with a fitness cost. We have shown that overexpression of the MexEF-OprN efflux pump does not decrease the fitness of a resistant Pseudomonas aeruginosa strain compared to its wild-type counterpart. This lack of fitness cost was associated with a metabolic rewiring that includes increased expression of the anaerobic nitrate respiratory chain when cells are growing under fully aerobic conditions. It was not clear whether this metabolic compensation was exclusive to strains overexpressing MexEF-OprN or if it extended to other resistant strains that overexpress similar systems. To answer this question, we studied a set of P. aeruginosa mutants that independently overexpress the MexAB-OprM, MexCD-OprJ, or MexXY efflux pumps. We observed increased expression of the anaerobic nitrate respiratory chain in all cases, with a concomitant increase in NO3 consumption and NO production. These efflux pumps are proton/substrate antiporters, and their overexpression may lead to intracellular H+ accumulation, which may in turn offset the pH homeostasis. Indeed, all studied mutants showed a decrease in intracellular pH under anaerobic conditions. The fastest way to eliminate the excess of protons is by increasing oxygen consumption, a feature also displayed by all analyzed mutants. Taken together, our results support metabolic rewiring as a general mechanism to avoid the fitness costs derived from overexpression of P. aeruginosa multidrug efflux pumps. The development of drugs that block this metabolic “reaccommodation” might help in reducing the persistence and spread of antibiotic resistance elements among bacterial populations. IMPORTANCE It is widely accepted that the acquisition of resistance confers a fitness cost in such a way that in the absence of antibiotics, resistant populations will be outcompeted by susceptible ones. Based on this assumption, antibiotic cycling regimes have been proposed in the belief that they will reduce the persistence and spread of resistance among bacterial pathogens. Unfortunately, trials testing this possibility have frequently failed, indicating that resistant microorganisms are not always outcompeted by susceptible ones. Indeed, some mutations do not result in a fitness cost, and in case they do, the cost may be compensated for by a secondary mutation. Here we describe an alternative nonmutational mechanism for compensating for fitness costs, which consists of the metabolic rewiring of resistant mutants. Deciphering the mechanisms involved in the compensation of fitness costs of antibiotic-resistant mutants may help in the development of drugs that will reduce the persistence of resistance by increasing said costs.Jorge Olivares PachecoCarolina Alvarez-OrtegaManuel Alcalde RicoJosé Luis MartínezAmerican Society for MicrobiologyarticlePseudomonas aeruginosaantibiotic resistanceefflux pumpsfitness costsMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pseudomonas aeruginosa antibiotic resistance efflux pumps fitness costs Microbiology QR1-502
spellingShingle	Pseudomonas aeruginosa antibiotic resistance efflux pumps fitness costs Microbiology QR1-502 Jorge Olivares Pacheco Carolina Alvarez-Ortega Manuel Alcalde Rico José Luis Martínez Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps
description	ABSTRACT It is generally assumed that the acquisition of antibiotic resistance is associated with a fitness cost. We have shown that overexpression of the MexEF-OprN efflux pump does not decrease the fitness of a resistant Pseudomonas aeruginosa strain compared to its wild-type counterpart. This lack of fitness cost was associated with a metabolic rewiring that includes increased expression of the anaerobic nitrate respiratory chain when cells are growing under fully aerobic conditions. It was not clear whether this metabolic compensation was exclusive to strains overexpressing MexEF-OprN or if it extended to other resistant strains that overexpress similar systems. To answer this question, we studied a set of P. aeruginosa mutants that independently overexpress the MexAB-OprM, MexCD-OprJ, or MexXY efflux pumps. We observed increased expression of the anaerobic nitrate respiratory chain in all cases, with a concomitant increase in NO3 consumption and NO production. These efflux pumps are proton/substrate antiporters, and their overexpression may lead to intracellular H+ accumulation, which may in turn offset the pH homeostasis. Indeed, all studied mutants showed a decrease in intracellular pH under anaerobic conditions. The fastest way to eliminate the excess of protons is by increasing oxygen consumption, a feature also displayed by all analyzed mutants. Taken together, our results support metabolic rewiring as a general mechanism to avoid the fitness costs derived from overexpression of P. aeruginosa multidrug efflux pumps. The development of drugs that block this metabolic “reaccommodation” might help in reducing the persistence and spread of antibiotic resistance elements among bacterial populations. IMPORTANCE It is widely accepted that the acquisition of resistance confers a fitness cost in such a way that in the absence of antibiotics, resistant populations will be outcompeted by susceptible ones. Based on this assumption, antibiotic cycling regimes have been proposed in the belief that they will reduce the persistence and spread of resistance among bacterial pathogens. Unfortunately, trials testing this possibility have frequently failed, indicating that resistant microorganisms are not always outcompeted by susceptible ones. Indeed, some mutations do not result in a fitness cost, and in case they do, the cost may be compensated for by a secondary mutation. Here we describe an alternative nonmutational mechanism for compensating for fitness costs, which consists of the metabolic rewiring of resistant mutants. Deciphering the mechanisms involved in the compensation of fitness costs of antibiotic-resistant mutants may help in the development of drugs that will reduce the persistence of resistance by increasing said costs.
format	article
author	Jorge Olivares Pacheco Carolina Alvarez-Ortega Manuel Alcalde Rico José Luis Martínez
author_facet	Jorge Olivares Pacheco Carolina Alvarez-Ortega Manuel Alcalde Rico José Luis Martínez
author_sort	Jorge Olivares Pacheco
title	Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps
title_short	Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps
title_full	Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps
title_fullStr	Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps
title_full_unstemmed	Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps
title_sort	metabolic compensation of fitness costs is a general outcome for antibiotic-resistant <italic toggle="yes">pseudomonas aeruginosa</italic> mutants overexpressing efflux pumps
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/81c0d553a1c8444da725d9b2574b3ab4
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Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant <italic toggle="yes">Pseudomonas aeruginosa</italic> Mutants Overexpressing Efflux Pumps

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