Enhancing innate immune defense against Staphylococcus aureus infection by therapeutic targeting of virulence regulation

Staphylococcus aureus is a medically significant pathogen that uses both cell-associated and secreted virulence factors to evade innate immune host defense. Because antibiotic resistance is an emerging and increasing problem with this pathogen, an alternative strategy for ameliorating the infection is to enhance host defense by inhibiting production of these virulence factors. We screened libraries of small molecules for inhibition of a pheromone-dependent quorum sensing operon, agr, which regulates expression of over 80 different genes including toxins and capsule that directly antagonize phagocyte-dependent host defense. A uricosuric drug used to treat gout, benzbromarone, inhibited pheromone dependent virulence without affecting bacterial viability in multiple S. aureus strains. When complexed with cyclodextrin as a vehicle, it inhibited S. aureus infection in a mouse model of dermonecrosis. More detailed in vitro studies revealed that the drug/cyclodextrin complex affected expression of both cell-associated and secreted virulence factors making the bacteria more susceptible to killing by oxidants and acid. Even after 50 generations of bacterial growth in the presence of benzbromarone, pheromone dependent virulence was still inhibited in the presence of the drug. These data indicate that signaling in bacterial pathogens can be targeted to enable killing and clearance by the innate immune system while limiting the development of induced resistance.