The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
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 togeth...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
American Society for Microbiology
2019-11-01
|
Series: | mBio |
Subjects: | |
Online Access: | https://doi.org/10.1128/mBio.01658-19 |
id |
doaj-f0e16c3ca043419491c389bb9c8c9175 |
---|---|
record_format |
Article |
spelling |
doaj-f0e16c3ca043419491c389bb9c8c91752021-07-02T09:46:30ZengAmerican Society for MicrobiologymBio2150-75112019-11-01106e01658-1910.1128/mBio.01658-19The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic InfectionDongzhu MaJonathan B. MandellNiles P. DoneganAmbrose L. CheungWanyan MaScott RothenbergerRobert M. Q. ShanksAnthony R. RichardsonKenneth L. UrishSurgical 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.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.https://doi.org/10.1128/mBio.01658-19surgical infectionbiofilmmazfstaphylococcus aureustoxin-antitoxin (ta) systemsicaadbcperiprosthetic joint infectionsurgical infection |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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 Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection mBio surgical infection biofilm mazf staphylococcus aureus toxin-antitoxin (ta) systems icaadbc periprosthetic joint infection surgical infection |
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 Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection |
title_short |
The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection |
title_full |
The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection |
title_fullStr |
The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection |
title_full_unstemmed |
The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection |
title_sort |
toxin-antitoxin mazef drives staphylococcus aureus biofilm formation, antibiotic tolerance, and chronic infection |
publisher |
American Society for Microbiology |
series |
mBio |
issn |
2150-7511 |
publishDate |
2019-11-01 |
description |
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.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. |
topic |
surgical infection biofilm mazf staphylococcus aureus toxin-antitoxin (ta) systems icaadbc periprosthetic joint infection surgical infection |
url |
https://doi.org/10.1128/mBio.01658-19 |
work_keys_str_mv |
AT dongzhuma thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT jonathanbmandell thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT nilespdonegan thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT ambroselcheung thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT wanyanma thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT scottrothenberger thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT robertmqshanks thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT anthonyrrichardson thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT kennethlurish thetoxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT dongzhuma toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT jonathanbmandell toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT nilespdonegan toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT ambroselcheung toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT wanyanma toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT scottrothenberger toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT robertmqshanks toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT anthonyrrichardson toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection AT kennethlurish toxinantitoxinmazefdrivesstaphylococcusaureusbiofilmformationantibiotictoleranceandchronicinfection |
_version_ |
1721332925383835648 |