The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection

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 biofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function in is controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in three strains to their corresponding strains with disruption of expression. Strains lacking production showed increased biofilm growth and decreased biofilm antibiotic tolerance. Deletion of in the ::Tn background suppressed the growth phenotype observed with -disrupted strains, suggesting the phenotype was dependent. We confirmed these phenotypes in our murine animal model. Loss of resulted in increased bacterial burden and decreased survival rate of mice compared to its wild-type strain demonstrating that loss of the gene caused an increase in virulence. Although lack of gene expression increased virulence, it was more susceptible to antibiotics Combined, the ability of 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. Surgical infections are one of the most common types of infections encountered in a hospital. 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 , a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allows 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.