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Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved numerous antimicrobial resistance mechanisms and is identified as a serious public health threat by the World Health Organization and U.S. Centers for Disease Control and Prevention. The glycopeptide vancomycin (VAN) remains a cornerston...

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Autores principales: Kumaraswamy, Monika, Wiull, Kamilla, Joshi, Bishnu, Sakoulas, George, Kousha, Armin, Vaaje-Kolstad, Gustav, Johannessen, Mona, Hegstad, Kristin, Nizet, Victor, Askarian, Fatemeh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539228/
https://www.ncbi.nlm.nih.gov/pubmed/34683376
http://dx.doi.org/10.3390/microorganisms9102055
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author Kumaraswamy, Monika
Wiull, Kamilla
Joshi, Bishnu
Sakoulas, George
Kousha, Armin
Vaaje-Kolstad, Gustav
Johannessen, Mona
Hegstad, Kristin
Nizet, Victor
Askarian, Fatemeh
author_facet Kumaraswamy, Monika
Wiull, Kamilla
Joshi, Bishnu
Sakoulas, George
Kousha, Armin
Vaaje-Kolstad, Gustav
Johannessen, Mona
Hegstad, Kristin
Nizet, Victor
Askarian, Fatemeh
author_sort Kumaraswamy, Monika
collection PubMed
description Methicillin-resistant Staphylococcus aureus (MRSA) has evolved numerous antimicrobial resistance mechanisms and is identified as a serious public health threat by the World Health Organization and U.S. Centers for Disease Control and Prevention. The glycopeptide vancomycin (VAN) remains a cornerstone of therapy for severe MRSA infections despite increasing reports of therapeutic failure in hospitalized patients with bacteremia or pneumonia. Recently, the role of released bacterial-derived membrane vesicles (MVs) in antibiotic resistance has garnered attention. Here we examined the effect of exogenous MRSA-derived MVs on VAN activity against MRSA in vitro, using minimum inhibitory concentration and checkerboard assays, and ex vivo, incorporating components of host innate immunity such as neutrophils and serum complement present in blood. Additionally, the proteome of MVs from VAN-exposed MRSA was characterized to determine if protein expression was altered. The presence of MVs increased the VAN MIC against MRSA to values where clinical failure is commonly observed. Furthermore, the presence of MVs increased survival of MRSA pre-treated with sub-MIC concentrations of VAN in whole blood and upon exposure to human neutrophils but not human serum. Unbiased proteomic analysis also showed an elevated expression of MV proteins associated with antibiotic resistance (e.g., marR) or proteins that are functionally linked to cell membrane/wall metabolism. Together, our findings indicate MRSA-derived MVs are capable of lowering susceptibility of the pathogen to VAN, whole-blood- and neutrophil-mediated killing, a new pharmacodynamic consideration for a drug increasingly linked to clinical treatment failures.
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spelling pubmed-85392282021-10-24 Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus Kumaraswamy, Monika Wiull, Kamilla Joshi, Bishnu Sakoulas, George Kousha, Armin Vaaje-Kolstad, Gustav Johannessen, Mona Hegstad, Kristin Nizet, Victor Askarian, Fatemeh Microorganisms Article Methicillin-resistant Staphylococcus aureus (MRSA) has evolved numerous antimicrobial resistance mechanisms and is identified as a serious public health threat by the World Health Organization and U.S. Centers for Disease Control and Prevention. The glycopeptide vancomycin (VAN) remains a cornerstone of therapy for severe MRSA infections despite increasing reports of therapeutic failure in hospitalized patients with bacteremia or pneumonia. Recently, the role of released bacterial-derived membrane vesicles (MVs) in antibiotic resistance has garnered attention. Here we examined the effect of exogenous MRSA-derived MVs on VAN activity against MRSA in vitro, using minimum inhibitory concentration and checkerboard assays, and ex vivo, incorporating components of host innate immunity such as neutrophils and serum complement present in blood. Additionally, the proteome of MVs from VAN-exposed MRSA was characterized to determine if protein expression was altered. The presence of MVs increased the VAN MIC against MRSA to values where clinical failure is commonly observed. Furthermore, the presence of MVs increased survival of MRSA pre-treated with sub-MIC concentrations of VAN in whole blood and upon exposure to human neutrophils but not human serum. Unbiased proteomic analysis also showed an elevated expression of MV proteins associated with antibiotic resistance (e.g., marR) or proteins that are functionally linked to cell membrane/wall metabolism. Together, our findings indicate MRSA-derived MVs are capable of lowering susceptibility of the pathogen to VAN, whole-blood- and neutrophil-mediated killing, a new pharmacodynamic consideration for a drug increasingly linked to clinical treatment failures. MDPI 2021-09-29 /pmc/articles/PMC8539228/ /pubmed/34683376 http://dx.doi.org/10.3390/microorganisms9102055 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kumaraswamy, Monika
Wiull, Kamilla
Joshi, Bishnu
Sakoulas, George
Kousha, Armin
Vaaje-Kolstad, Gustav
Johannessen, Mona
Hegstad, Kristin
Nizet, Victor
Askarian, Fatemeh
Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus
title Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus
title_full Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus
title_fullStr Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus
title_full_unstemmed Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus
title_short Bacterial Membrane-Derived Vesicles Attenuate Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus
title_sort bacterial membrane-derived vesicles attenuate vancomycin activity against methicillin-resistant staphylococcus aureus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539228/
https://www.ncbi.nlm.nih.gov/pubmed/34683376
http://dx.doi.org/10.3390/microorganisms9102055
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