Infectious diarrhea is a complex syndrome caused by many viruses, parasites, fungi and bacteria such as Salmonella. Salmonellosis itself encompasses a spectrum of clinical diseases that range from enteric fever, a serious condition that kills about 600,000 people a year, to non-typhoidal zoonotic infections that affect more than a million Americans annually, including active military servicemen and the veteran population. Treatment of Salmonella and medically important Gram- negative rods is often complicated by the increasing resistance of pathogenic bacteria to the antibiotics used in the clinic. Efflux pumps, modifying enzymes, and altered targets enhance bacterial resistance to antibiotics. In addition, the effectiveness of antibiotic therapy is greatly influenced by the metabolic pathways used by the bacterial cell and by the adaptive responses of the organism to environmental stresses. Recent investigations from our laboratory and others have shown that nitric oxide produced endogenously or in the innate response of macrophages elicits antibiotic tolerance in a variety of Gram-positive and -negative microorganisms. The protective response elicited by nitric oxide appears to be associated the ability of this diatomic radical to elicit antioxidative responses. Preliminary data presented in his application has identified the zinc finger in the globular domain of DksA as a bone fide sensor of oxidative and nitrosative stress. We hypothesize that sensing of reactive species by the DksA zinc finger promotes antioxidant and antinitrosative defenses, antibiotic resistance and the pathogenicity of Salmonella.
Aim 1 will determine the molecular mechanisms that mediate sensing of oxidative and nitrosative stress by the DksA zinc finger.
Aims 2 and 3 will identify how DksA-regulated stringent response and cysteine biosynthesis foster Salmonella virulence, antioxidant defenses and antibiotic tolerance. These investigations will provide profound insights into the antioxidant and antinitrosative defenses of Salmonella that are critical for intracellula survival and virulence. This research will also help in the rational development of future prophylactic and therapeutic approaches for the treatment of a variety of Gram-negative, often antibiotic resistant, bacteria that cause high rates of morbidity and mortality in people around the globe, including veterans and patients in VA hospitals.
Non-typhoidal Salmonella enterica is a frequent cause of gastroenteritis in healthy individuals and a life- threatening systemic infection in people with HIV infection. Human-adapted Salmonella serovars cause serious and often fatal enteric (typhoid) fever. Medically important bacteria are becoming increasingly resistant to multiple antibiotics. Salmonella and antibiotic-resistant bacterial infections cause high rates of morbidity and mortality around the globe, including the men and women actively serving in the armed forces, veterans and patients in VA hospitals. The stringent response and the DksA RNA polymerase regulatory protein have recently been shown to increase resistance of Gram-negative bacteria such as Salmonella to oxidative stress, while increasing antibiotic tolerance. We have identified the zinc finger in Dks as a novel sensor of oxidative and nitrosative stress. Our proposal will characterize the molecular mechanisms by which sensing of reactive oxygen and nitrogen species by DksA zinc finger contributes to Salmonella virulence and antibiotic tolerance.
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