Structural Modification of Daptomycin to Allow Anti-Pseudomonas Activity

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 DESCRIPTION (provided by applicant): Pseudomonas is a common aerobic, gram-negative, coccobacillis. Current concerns with P. aeruginosa are both the frequency of the organism as a very common cause of nosocomial pneumonia and the emerging difficulty in treating it. Since the advent of antibiotics, P. aeruginosa has developed progressive resistance to the usual treatments. The siderophore ("iron carrier") molecule targeting technology translates P. aeruginosa's obligate iron needs and mechanisms for iron foraging into a therapeutic agent. Bacterial iron acquisition is essential for pathogenicity and provides an attractive and little-use target for developing microbe-selective therapeutics. Because of selective siderophore recognition and transport needed for bacterial growth advantage, we will test a siderophore previously shown to be active in targeting antibiotics to pseudomonas. Many attempts at siderophore targeting have failed because of poor structural matching of the siderophore to the native ligands. Hsiri Therapeutics' chemists have put molecular recognition as the primary criterion for designing sideromycin-antibiotic conjugates. By these methods, Hsiri Therapeutics, LLC has recently demonstrated that the previously gram-positive specific antibiotic, daptomycin, can be modified for treatment against the gram-negative bacterium, Acinetobacter baumannii. This transformation was done with the addition of a targeting molecule, a siderophore compound, to the daptomycin molecule. The siderophore linked to the daptomycin was designed to be specific for acinetobacter and this specificity was achieved. In like manner, Hsiri scientists have designed an antibiotic substitution that targets Pseudomonas aeruginosa. This proposal would support the synthesis of this agent and the initial characterization of the compound in vitro and in vivo. Our approach through four specific aims will be to extend the work we have done with the tripodal catecholate - entereobactin mimetic with beta-lactam antibiotics and extend it to daptomycin. Once purified, this new molecule will be assessed with standard methods for both in vitro and in vivo activity. Additionally, detailed tolerability in mic will be evaluated with this compound and a bacterial clearance study (aka bacterial burden study) will be done to ensure full bacterial killing and clearance in an experimental murine sepsis model with pseudomonas.