In their natural environment pathogenic bacteria are persistently exposed to reactive oxygen and nitrogen species generated by a host. Forced to withstand this stress, pathogens have developed a sophisticated defense system. Despite extensive research, the role of nitric oxide (NO) in host-pathogen interaction remains unclear. Various reports have registered both deleterious and cytoprotective effects of NO. Our preliminary data indicate that Gram-positive bacteria employ exogenous NO to immediately activate their oxidative stress defense system by a novel mechanism. The objectives of this proposal are to clarify the role of host generated NO for pathogen survival and design the methods to enhance the bactericidal properties of NO. Our proposed experiments are based on sufficient preliminary data and expected to yield, within provided time frame, significant results which will be applicable for treating a broad spectrum of pathogens.
Specific aims are: 1. Understand the mechanism of NO-mediated bacterial cell protection and its role in host-pathogen interaction. Our in vitro and in vivo studies demonstrate that a key enzyme of bacterial oxidative stress defense system, the catalase, is strongly and directly activated by physiological amounts of NO. Using Staphylococcus aureus as a model pathogen, we will determine a mechanism of NO-dependent catalase activation and its role in bacteria evasion of immune response. It is further proposed using small molecules to compromise the bacterial catalase activation thus improving the effectiveness of the innate immune response to a variety of Gram-positive pathogens. 2. Design specific NO-inducible antibiotics. Since pathogenic bacteria are exposed to large quantities of host-derived NO and also generate their own NO, the design of specific small molecules that become cytotoxic upon reaction with NO provides a conceptually new way to combat infection. Our preliminary studies demonstrate that the hydrophobic derivatives of 5-aminonaphtalenesulfonamides (ANSA) can efficiently suppress various enzymatic activities upon interaction with NO and posses strong bactericidal effect. It is further proposed to develop selective antimicrobial compounds based on ANSA.
| Gusarov, Ivan; Nudler, Evgeny (2005) NO-mediated cytoprotection: instant adaptation to oxidative stress in bacteria. Proc Natl Acad Sci U S A 102:13855-60 |
