GENETIC AND REDOX DETERMINANTS OF NITRIC-OXIDE CYTOTOXICITY IN A SALMONELLA-TYPHIMURIUM MODEL

Paradoxically, nitric oxide (NO) has been found to exhibit cytotoxic, antiproliferative, or cytoprotective activity under different conditio ns. We have utilized Salmonella mutants deficient in antioxidant defen ses or peptide transport to gain insights into NO actions. Comparison of three NO donor compounds reveals distinct and independent cellular responses associated with specific redox forms of NO. The peroxynitrit e (OONO-) generator 3-morpholinosydnonmine hydrochloride mediates oxyg en-dependent Salmonella killing, whereas S-nitrosoglutathione (GSNO) c auses oxygen-independent cytostasis, and the NO donor diethylenetriami ne-nitric oxide adduct has no antibacterial activity. GSNO has the gre atest activity for stationary cells, a characteristic relevant to late nt or intracellular pathogens. Moreover, the cytostatic activity of GS NO may best correlate with antiproliferative or antimicrobial effects of NO, which are unassociated with overt cell injury. dpp mutants defe ctive in active dipeptide transport are resistant to GSNO, implicating heterolytic NO+ transfer rather than homolytic NO release in the mech anism of cytostasis. This transport system may provide a specific path way for GSNO-mediated signaling in biological systems. The redox state and associated carrier molecules are critical determinants of NO acti vity.