Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics

ABSTRACT Antimicrobial peptides (AMPs) are essential components of the innate immune system and have been proposed as promising therapeutic agents against drug-resistant microbes. AMPs possess a rapid bactericidal mode of action and can interact with different targets, but bacteria can also avoid th...

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Autores principales:	Paula Blanco, Karin Hjort, José L. Martínez, Dan I. Andersson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Stenotrophomonas antibiotic resistance antimicrobial peptides cross-resistance drug resistance evolution Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c8646e9dc1c24940802c1363f18c5c78
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spelling	oai:doaj.org-article:c8646e9dc1c24940802c1363f18c5c782021-11-15T15:30:58ZAntimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics10.1128/mSphere.00717-202379-5042https://doaj.org/article/c8646e9dc1c24940802c1363f18c5c782020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00717-20https://doaj.org/toc/2379-5042ABSTRACT Antimicrobial peptides (AMPs) are essential components of the innate immune system and have been proposed as promising therapeutic agents against drug-resistant microbes. AMPs possess a rapid bactericidal mode of action and can interact with different targets, but bacteria can also avoid their effect through a variety of resistance mechanisms. Apart from hampering treatment by the AMP itself, or that by other antibiotics in the case of cross-resistance, AMP resistance might also confer cross-resistance to innate human peptides and impair the anti-infective capability of the human host. A better understanding of how resistance to AMPs is acquired and the genetic mechanisms involved is needed before using these compounds as therapeutic agents. Using experimental evolution and whole-genome sequencing, we determined the genetic causes and the effect of acquired de novo resistance to three different AMPs in the opportunistic pathogen Stenotrophomonas maltophilia, a bacterium that is intrinsically resistant to a wide range of antibiotics. Our results show that AMP exposure selects for high-level resistance, generally without any reduction in bacterial fitness, conferred by mutations in different genes encoding enzymes, transporters, transcriptional regulators, and other functions. Cross-resistance to AMPs and to other antibiotic classes not used for selection, as well as collateral sensitivity, was observed for many of the evolved populations. The relative ease by which high-level AMP resistance is acquired, combined with the occurrence of cross-resistance to conventional antibiotics and the maintained bacterial fitness of the analyzed mutants, highlights the need for careful studies of S. maltophilia resistance evolution to clinically valuable AMPs. IMPORTANCE Stenotrophomonas maltophilia is an increasingly relevant multidrug-resistant (MDR) bacterium found, for example, in people with cystic fibrosis and associated with other respiratory infections and underlying pathologies. The infections caused by this nosocomial pathogen are difficult to treat due to the intrinsic resistance of this bacterium against a broad number of antibiotics. Therefore, new treatment options are needed, and considering the growing interest in using AMPs as alternative therapeutic compounds and the restricted number of antibiotics active against S. maltophilia, we addressed the potential for development of AMP resistance, the genetic mechanisms involved, and the physiological effects that acquisition of AMP resistance has on this opportunistic pathogen.Paula BlancoKarin HjortJosé L. MartínezDan I. AnderssonAmerican Society for MicrobiologyarticleStenotrophomonasantibiotic resistanceantimicrobial peptidescross-resistancedrug resistance evolutionMicrobiologyQR1-502ENmSphere, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Stenotrophomonas antibiotic resistance antimicrobial peptides cross-resistance drug resistance evolution Microbiology QR1-502
spellingShingle	Stenotrophomonas antibiotic resistance antimicrobial peptides cross-resistance drug resistance evolution Microbiology QR1-502 Paula Blanco Karin Hjort José L. Martínez Dan I. Andersson Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics
description	ABSTRACT Antimicrobial peptides (AMPs) are essential components of the innate immune system and have been proposed as promising therapeutic agents against drug-resistant microbes. AMPs possess a rapid bactericidal mode of action and can interact with different targets, but bacteria can also avoid their effect through a variety of resistance mechanisms. Apart from hampering treatment by the AMP itself, or that by other antibiotics in the case of cross-resistance, AMP resistance might also confer cross-resistance to innate human peptides and impair the anti-infective capability of the human host. A better understanding of how resistance to AMPs is acquired and the genetic mechanisms involved is needed before using these compounds as therapeutic agents. Using experimental evolution and whole-genome sequencing, we determined the genetic causes and the effect of acquired de novo resistance to three different AMPs in the opportunistic pathogen Stenotrophomonas maltophilia, a bacterium that is intrinsically resistant to a wide range of antibiotics. Our results show that AMP exposure selects for high-level resistance, generally without any reduction in bacterial fitness, conferred by mutations in different genes encoding enzymes, transporters, transcriptional regulators, and other functions. Cross-resistance to AMPs and to other antibiotic classes not used for selection, as well as collateral sensitivity, was observed for many of the evolved populations. The relative ease by which high-level AMP resistance is acquired, combined with the occurrence of cross-resistance to conventional antibiotics and the maintained bacterial fitness of the analyzed mutants, highlights the need for careful studies of S. maltophilia resistance evolution to clinically valuable AMPs. IMPORTANCE Stenotrophomonas maltophilia is an increasingly relevant multidrug-resistant (MDR) bacterium found, for example, in people with cystic fibrosis and associated with other respiratory infections and underlying pathologies. The infections caused by this nosocomial pathogen are difficult to treat due to the intrinsic resistance of this bacterium against a broad number of antibiotics. Therefore, new treatment options are needed, and considering the growing interest in using AMPs as alternative therapeutic compounds and the restricted number of antibiotics active against S. maltophilia, we addressed the potential for development of AMP resistance, the genetic mechanisms involved, and the physiological effects that acquisition of AMP resistance has on this opportunistic pathogen.
format	article
author	Paula Blanco Karin Hjort José L. Martínez Dan I. Andersson
author_facet	Paula Blanco Karin Hjort José L. Martínez Dan I. Andersson
author_sort	Paula Blanco
title	Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics
title_short	Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics
title_full	Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics
title_fullStr	Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics
title_full_unstemmed	Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics
title_sort	antimicrobial peptide exposure selects for resistant and fit <named-content content-type="genus-species">stenotrophomonas maltophilia</named-content> mutants that show cross-resistance to antibiotics
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c8646e9dc1c24940802c1363f18c5c78
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Antimicrobial Peptide Exposure Selects for Resistant and Fit <named-content content-type="genus-species">Stenotrophomonas maltophilia</named-content> Mutants That Show Cross-Resistance to Antibiotics

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