Quorum Sensing

Multiple drug resistance poses a significant threat to public health worldwide, with a substantial increase in morbidity and mortality rates. Consequently, searching for novel strategies to control microbial pathogenicity is necessary. With the aid of auto-inducers (AIs), quorum sensing (QS) regulates bacterial virulence factors through cell-to-cell signaling networks. AIs are small signaling molecules produced during the stationary phase. When bacterial cultures reach a certain level of growth, these molecules regulate the expression of the bound genes by acting as mirrors that reflect the inoculum density.Gram-positive bacteria use the peptide derivatives of these signaling molecules, whereas Gram-negative bacteria use the fatty acid derivatives, and the majority of bacteria can use both types to modulate the expression of the target gene. Numerous natural and synthetic QS inhibitors (QSIs) have been developed to reduce microbial pathogenesis. Applications of QSI are vital to human health, as well as fisheries and aquaculture, agriculture, and water treatment. Video Abstract.

Antibiotic resistance is a major problem and a major global health concern. In total, there are 16 million deaths yearly from infectious diseases, and at least 65% of infectious diseases are caused by microbial communities that proliferate through the formation of biofilms. Antibiotic overuse has resulted in the evolution of multidrug-resistant (MDR) microbial strains. As a result, there is now much more interest in non-antibiotic therapies for bacterial infections. Among these revolutionary, non-traditional medications is quorum sensing inhibitors (QSIs). Bacterial cell-to-cell communication is known as quorum sensing (QS), and it is mediated by tiny diffusible signaling molecules known as autoinducers (AIs). QS is dependent on the density of the bacterial population. QS is used by Gram-negative and Gram-positive bacteria to control a wide range of processes; in both scenarios, QS entails the synthesis, identification, and reaction to signaling chemicals, also known as auto-inducers. Since the usual processes regulated by QS are the expression of virulence factors and the creation of biofilms, QS is being investigated as an alternative solution to antibiotic resistance. Consequently, the use of QS-inhibiting agents, such as QSIs and quorum quenching (QQ) enzymes, to interfere with QS seems like a good strategy to prevent bacterial infections. This review sheds light on QS inhibition strategy and mechanisms and discusses how using this approach can aid in winning the battle against resistant bacteria.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, 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 Δagr 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 Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. 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.

Infective endocarditis (IE) is a severe heart infection caused predominantly by Gram-positive bacteria forming biofilm on heart valves. While biofilm formation is central to disease progression, the underlying bacterial mechanisms remain poorly understood. Here, we identify the Fsr quorum sensing (QS) system of Enterococcus faecalis as an unexpected negative regulator of biofilm and pathogenesis in IE. Using microfluidic and in vivo models, we show that blood flow prevents Fsr activation in early IE, with Fsr induction occurring only later, once bacteria form biofilm microcolonies and become shielded from flow. Deletion of Fsr promotes robust biofilm growth, driven partly through the downregulation of GelE and SprE proteases, reprograms metabolism by upregulating lrgAB to enhance pyruvate utilization, and increases gentamicin tolerance in vivo. Furthermore, we show that GelE cleaves the human pro-IL-1β into an active form, suggesting a species-specific mechanism for inflammation modulation by QS. In support of these findings, analysis of IE patient cohorts shows that naturally occurring Fsr-deficient E. faecalis strains are associated with prolonged bacteremia. Overall, our findings provide insights into how host blood flow impacts QS activation, which, in turn, regulates pathogenesis in IE, and highlight the Fsr QS as a potential determinant of clinical disease course.