The Toxin Antitoxin MazEF DrivesStaphylococcus aureusChronic Infection

Abstract

48Staphylococcus aureus is the major organism responsible for surgical implant infections. 49Antimicrobial treatment of these infections often fails leading to expensive surgical intervention 50and increased risk of mortality to the patient. The challenge in treating these infections is 51 associated with the high tolerance of S. aureus biofilm to antibiotics. MazEF, a toxin-antitoxin 52 system, is thought to be an important regulator of this phenotype, but its physiological function 53 in S. aureus is controversial. Here, we examined the role of MazEF in developing chronic 54infections by comparing growth and antibiotic tolerance phenotypes in three S. aureus strains 55to their corresponding strains with disruption of mazF expression. Strains lacking mazF 56 production showed increased biofilm growth, and decreased biofilm antibiotic tolerance. 57Deletion of icaADBC in the mazF::tn background suppressed the growth phenotype observed 58with mazF-disrupted strains, suggesting the phenotype was ica-dependent. We confirmed 59 these phenotypes in our murine animal model. Loss of mazF resulted in increased bacterial 60 burden and decreased survival rate compared to its wild-type strain demonstrating that loss of 61the mazF gene caused an increase in S. aureus virulence. Although lack of mazF gene 62 expression increased S. aureus virulence, it was more susceptible to antibiotics in vivo. 63Combined, the ability of mazF to inhibit biofilm formation and promote biofilm antibiotic 64tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to 65 eradicate with antibiotics alone. 66 67Importance 68Surgical infections are one of the most common types of infections obtained in a hospital. 69Staphylococcus aureus is the most common pathogen associated with this infection. These 70infections are resilient and difficult to eradicate as the bacteria form a biofilm, a community of 71 bacteria held together by an extracellular matrix. Compared to bacteria floating in liquid, 72bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria 73 develop this resistance and establish a chronic infection is unknown. We demonstrate that 74 mazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic 75 tolerance which allows S. aureus to transition from an acute to chronic infection that cannot be 76 eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more 77 tolerant to antibiotics but makes the bacteria more tolerant to the host. 78 79

Type II Antitoxin HigA Is a Key Virulence Regulator in Pseudomonas aeruginosa

“…Several studies have reported the essential roles of the type II TA pairs such as VapBC, MazEF, and RelBE in bacterial pathogenesis. 10,11,16 Moreover, HigA plays a vital role in biofilm formation, iron uptake, and carbon metabolism in P. aeruginosa. 14,15,17 Therefore, we investigated the contributions of higA in P. aeruginosa infection by comparing the virulence of the WT, ΔhigA, and higB deletion (ΔhigB) strains in a Galleria mellonella infection model.…”

“…Several studies have reported the essential roles of the type II TA pairs such as VapBC, MazEF, and RelBE in bacterial pathogenesis. ,, Moreover, HigA plays a vital role in biofilm formation, iron uptake, and carbon metabolism in P. aeruginosa .…”

“…tuberculosis to adapt to host environments . Moreover, the type II MazEF TA system was found to play a role in surgical infections due to Staphylococcus aureus, in which the decreased antitoxin MazF has been found to enhance biofilm formation and bacterial burden in mice . However, the mechanisms underlying how TA systems modulate the virulence genes and pathogenesis remain unclear.…”