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Microbiology and Molecular Genetics Program
B.S., 2007, Northeastern University, Boston, MA
Thesis Advisor: Karl Drlica, Ph.D.
Department of Microbiology and Molecular Genetics
Tuesday, April 22, 2014
10:00 A.M., ICPH-Auditorium
Antimicrobial lethality is proposed to be promoted by a cascade of reactive oxygen species (ROS) that starts with the accumulation of superoxide and leads to the formation of highly reactive hydroxyl radical. The soxRS regulon serves as a major cellular defense against superoxide. Deficiencies in soxS, a transcriptional activator of the regulon, and nfo, a known target of soxS that repairs ROS-mediated DNA damage, increased the lethal activity of antimicrobials and UV irradiation. Moreover, E. coli plated on LB agar containing a subinhibitory concentration of thiourea, a hydroxyl radical scavenger, exhibited an increase in survival relative to plating on LB agar lacking thiourea after treatment with antimicrobials and UV irradiation. Thus, bacterial cells progress along an ROS-mediated death pathway even after the initial stressor is removed. Paradoxically, pretreatment with subinhibitory concentrations of plumagin, or paraquat, metabolic generators of superoxide, reduced the lethal action of several classes of antimicrobials, lowered quinolone-mediated ROS accumulation, and increased persister cell formation. In addition, pretreatment with superoxide generators increased antimicrobial MIC through activation of the AcrAB-TolC MDR efflux pump. These data suggest that low to moderate levels of superoxide can induced protective pathways that include DNA repair and antimicrobial efflux, while higher levels of superoxide initiate an ROS cascade that leads to hydroxyl radical production and cell death. This protective role of superoxide, when combined with its known destructive action, leads to the conclusion that superoxide is a bifunctional factor in the lethal stress response: the level of superoxide helps make the decision whether damage is repaired or cells self-destruct. Understanding the molecular mechanism underlying this decision may lead to novel ways to control bacterial infections.