The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection

ABSTRACT Staphylococcus aureus is the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails, leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associat...

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Autores principales:	Dongzhu Ma, Jonathan B. Mandell, Niles P. Donegan, Ambrose L. Cheung, Wanyan Ma, Scott Rothenberger, Robert M. Q. Shanks, Anthony R. Richardson, Kenneth L. Urish
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	surgical infection biofilm MazF Staphylococcus aureus toxin-antitoxin (TA) systems icaADBC Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f0c9f228eed34dbda35ad3ab5c193533
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spelling	oai:doaj.org-article:f0c9f228eed34dbda35ad3ab5c1935332021-11-15T15:54:45ZThe Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection10.1128/mBio.01658-192150-7511https://doaj.org/article/f0c9f228eed34dbda35ad3ab5c1935332019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01658-19https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails, leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associated with the high tolerance of S. aureus biofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function in S. aureus is controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in three S. aureus strains to their corresponding strains with disruption of mazF expression. Strains lacking mazF production showed increased biofilm growth and decreased biofilm antibiotic tolerance. Deletion of icaADBC in the mazF::Tn background suppressed the growth phenotype observed with mazF-disrupted strains, suggesting the phenotype was ica dependent. We confirmed these phenotypes in our murine animal model. Loss of mazF resulted in increased bacterial burden and decreased survival rate of mice compared to its wild-type strain demonstrating that loss of the mazF gene caused an increase in S. aureus virulence. Although lack of mazF gene expression increased S. aureus virulence, it was more susceptible to antibiotics in vivo. Combined, the ability of mazF to inhibit biofilm formation and promote biofilm antibiotic tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to eradicate with antibiotics alone. IMPORTANCE Surgical infections are one of the most common types of infections encountered in a hospital. Staphylococcus aureus is the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate, as the bacteria form biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria that are planktonic, bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria develop this resistance and establish a chronic infection is unknown. We demonstrate that mazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allows S. aureus to transition from an acute to chronic infection that cannot be eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more tolerant to antibiotics but makes the bacteria more tolerant to the host.Dongzhu MaJonathan B. MandellNiles P. DoneganAmbrose L. CheungWanyan MaScott RothenbergerRobert M. Q. ShanksAnthony R. RichardsonKenneth L. UrishAmerican Society for Microbiologyarticlesurgical infectionbiofilmMazFStaphylococcus aureustoxin-antitoxin (TA) systemsicaADBCMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	surgical infection biofilm MazF Staphylococcus aureus toxin-antitoxin (TA) systems icaADBC Microbiology QR1-502
spellingShingle	surgical infection biofilm MazF Staphylococcus aureus toxin-antitoxin (TA) systems icaADBC Microbiology QR1-502 Dongzhu Ma Jonathan B. Mandell Niles P. Donegan Ambrose L. Cheung Wanyan Ma Scott Rothenberger Robert M. Q. Shanks Anthony R. Richardson Kenneth L. Urish The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
description	ABSTRACT Staphylococcus aureus is the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails, leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associated with the high tolerance of S. aureus biofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function in S. aureus is controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in three S. aureus strains to their corresponding strains with disruption of mazF expression. Strains lacking mazF production showed increased biofilm growth and decreased biofilm antibiotic tolerance. Deletion of icaADBC in the mazF::Tn background suppressed the growth phenotype observed with mazF-disrupted strains, suggesting the phenotype was ica dependent. We confirmed these phenotypes in our murine animal model. Loss of mazF resulted in increased bacterial burden and decreased survival rate of mice compared to its wild-type strain demonstrating that loss of the mazF gene caused an increase in S. aureus virulence. Although lack of mazF gene expression increased S. aureus virulence, it was more susceptible to antibiotics in vivo. Combined, the ability of mazF to inhibit biofilm formation and promote biofilm antibiotic tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to eradicate with antibiotics alone. IMPORTANCE Surgical infections are one of the most common types of infections encountered in a hospital. Staphylococcus aureus is the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate, as the bacteria form biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria that are planktonic, bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria develop this resistance and establish a chronic infection is unknown. We demonstrate that mazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allows S. aureus to transition from an acute to chronic infection that cannot be eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more tolerant to antibiotics but makes the bacteria more tolerant to the host.
format	article
author	Dongzhu Ma Jonathan B. Mandell Niles P. Donegan Ambrose L. Cheung Wanyan Ma Scott Rothenberger Robert M. Q. Shanks Anthony R. Richardson Kenneth L. Urish
author_facet	Dongzhu Ma Jonathan B. Mandell Niles P. Donegan Ambrose L. Cheung Wanyan Ma Scott Rothenberger Robert M. Q. Shanks Anthony R. Richardson Kenneth L. Urish
author_sort	Dongzhu Ma
title	The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
title_short	The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
title_full	The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
title_fullStr	The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
title_full_unstemmed	The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
title_sort	toxin-antitoxin mazef drives <named-content content-type="genus-species">staphylococcus aureus</named-content> biofilm formation, antibiotic tolerance, and chronic infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/f0c9f228eed34dbda35ad3ab5c193533
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The Toxin-Antitoxin MazEF Drives <named-content content-type="genus-species">Staphylococcus aureus</named-content> Biofilm Formation, Antibiotic Tolerance, and Chronic Infection

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