Little is understood about the physiological or regulatory factors of Streptococcus pyogenes that enable switching between its commensal-like and virulent states. This proposal describes experimental approaches that seek to continue defining and characterizing quorum-sensing regulatory pathways that correspond to phenotypes consistent with the avirulent lifestyle of Streptococcus pyogenes (Group A Streptococcus; GAS). The quorum sensing network in Streptococcus pyogenes utilizing short hydrophobic peptide (SHP) pheromones and the pheromone receptors Rgg2 and Rgg3 regulates several phenotypes, including biofilm development, cell aggregation, aminoglycoside susceptibility, and lysozyme resistance, by an unknown mechanism. Our studies indicate that each of these phenotypes depend upon the expression of a small protein of unknown function. We hypothesize that this protein, referred to as StcB, is an inhibitor of an enzyme(s) that targets peptidoglycan bonds of the cell wall. Additional studies indicate the target of StcB is a murein hydrolase enzyme, called Isp, that contains cysteine and histidine-dependent amidohydrolase/peptidase (CHAP) and acetylglucosaminidase domains. Governance of StcB and Isp by the Rgg2/3 quorum sensing pathway accounts for significant changes to the bacterial cell surface, resulting in differential attachment to fibronectin and epithelial cells, and differential immuno- modulatory activities. This proposal seeks to elucidate the mechanisms by which StcB and Isp enzymes account for biochemical changes to the surface of S. pyogenes, how these changes lead to differential activity of surface structures and proteins, and how these changes affect the ability of S. pyogenes to colonize the host and modulate immune activities.
Asymptomatic carriage of many bacterial pathogens in the human body serves as the reservoir for periodic outbreak of infectious disease, yet little is understood about the physiological and regulatory factors that sustain asymptomatic relationships, or about the signals accounting for the switch between commensal and virulent states. This proposal describes experimental approaches that will define and characterize recently discovered communication pathways and the physiological states under their regulation in Streptococcus pyogenes (Group A Streptococcus; GAS). Our studies are likely to provide mechanistic explanations for how these bacteria transition between harmless and harmful states. Our studies have identified small-molecule modulators of these communication pathways and thus may provide new leads in the development of alternative therapeutics to antibiotics as a way to treat infectious diseases.
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