Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H ₂ O ₂ , a crucial host defense against S. aureus . We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δ agr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δ agr strains to lethal H ₂ O ₂ doses. Increased survival of wild-type agr cells during H ₂ O ₂ exposure required sodA , which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δ agr cells from killing by H ₂ O ₂ . Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr -mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient ( Cybb ^-/- ) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.
Competing Interests: MP, AP, GP, AP, JK, EZ, RU, TK, CZ, AH, JS, GW, JK, JC, AR, JW, CN, DL, DP, AP, XZ, KD, IY No competing interests declared, AD Inventor on patents and patent applications (US8431, 687B2; US2019135900 A1; EP4313303A1) filed by New York University, which are currently under commercial license to Janssen Biotech Inc. Janssen Biotech Inc provides research funding and other payments associated with a licensing agreement. These patents pertain solely to the development of vaccines and therapeutics targeting S. aureus toxins and are unrelated to the content presented in this work, VT Has received honoraria from Pfizer and MedImmune, and is an inventor on patents and patent applications filed by New York University,(US8431, 687B2; US2019135900 A1; EP4313303A1) which are currently under commercial license to Janssen Biotech Inc. Janssen Biotech Inc provides research funding and other payments associated with a licensing agreement, BS Has consulted for Basilea Pharmaceutica
(© 2023, Podkowik et al.)