Maduta, C. S. | Search bioRxiv

bioRxiv2024

Discovery of an anti-virulence compound that targets the Staphylococcus aureus SaeRS two-component system to inhibit toxic shock syndrome toxin 1 (TSST-1) production

Menstrual toxic shock syndrome (mTSS) is a rare but severe disorder associated with the use of menstrual products such as high-absorbency tampons and is caused by Staphylococcus aureus strains that produce the toxic shock syndrome toxin-1 (TSST-1) superantigen. Herein, we screened a library of 3920 small bioactive molecules for the ability to inhibit transcription of the TSST-1 gene without inhibiting growth of S. aureus. The dominant positive regulator of TSST-1 is the SaeRS two-component system (TCS), and we identified phenazopyridine hydrochloride (PP-HCl) that repressed production of TSST-1 by inhibiting the kinase function of SaeS. PP-HCl competed with ATP for binding of the kinase SaeS leading to decreased phosphorylation of SaeR and reduced expression of TSST-1 as well as several other secreted virulence factors known to be regulated by SaeRS. PP-HCl targets virulence of S. aureus, but it also decreases the impact of TSST-1 on human lymphocytes without affecting the healthy vaginal microbiota. Our findings demonstrate the promising potential of PP-HCl as a therapeutic strategy against mTSS.

microbiology↗

bioRxiv2023

Vaginal Community State Types (CSTs) Alter Environmental Cues and Production of the Staphylococcus aureus Toxic Shock Syndrome Toxin-1 (TSST-1)

Menstrual toxic shock syndrome (mTSS) is a rare but life-threatening disease associated with use of high-absorbency tampons. The production of the Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1) is involved in nearly all cases of mTSS and is tightly controlled by regulators responding to the environment. In the prototypic mTSS strain S. aureus MN8, the major repressor of TSST-1 is the carbon catabolite protein A (CcpA), which responds to glucose concentrations in the vaginal tract. Healthy vaginal Lactobacillus species also depend on glucose for both growth and acidification of the vaginal environment through lactic acid production. We hypothesized that interactions between the vaginal microbiota (herein referred to as Community State Types, or CSTs) and MN8 depend on environmental cues, and that these interactions subsequently affect TSST-1 production. Using MN8 {Delta}1ccpA at various glucose levels, we demonstrate that the supernatants from different CSTs grown in vaginally defined media (VDM) significantly decrease tst expression. When co-culturing CST species with MN8 {Delta}ccpA, we show that L. jensenii completely inhibits TSST-1 production in conditions mimicking healthy menstruation or mTSS. Finally, we show that growing S. aureus in "unhealthy" or "transitional" CST supernatants results in higher IL-2 production from T cells. These findings suggest that dysbiotic CSTs may encourage TSST-1 production in the vaginal tract, and further indicates that the CSTs are likely important for the development of mTSS. IMPORTANCEIn this study, we investigate the impact of the vaginal microbiota against S. aureus in conditions mimicking the vaginal environment at various stages of the menstrual cycle. We demonstrate that L. jensenii can inhibit TSST-1 production, suggesting the potential for probiotic activity in treating mTSS. On the other side of the spectrum, "unhealthy" or "transient" bacteria such as G. vaginalis and L. iners support more TSST-1 production by S. aureus, suggesting that CSTs are important in the development of mTSS. This study sets forward a model for examining contact-independent interactions between pathogenic bacteria and the vaginal microbiota. It also demonstrates the necessity of replicating the environment when studying one as dynamic as the vagina.

microbiology↗