Development of Streptothricin Class Antimicrobials as Novel Therapeutics

Acinetobacter baumannii and carbapenem-resistant Enterobacteriaceae are among an emerging class ofmultidrug-resistant, Gram-negative bacterial pathogens that are often either effectively untreatable or onlytreatable with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibioticresistance threat level. New anti-infective strategies are urgently needed. Streptothricin is an antibiotic that wasdiscovered over 70 years ago. It has an impressive activity spectrum against otherwise resistant Gram-negativepathogens. However, initial concern around toxicities and the availability of alternative antibiotics precluded itsdevelopment, and it has largely been forgotten. Moreover, in the past, when it was still considered the basis ofa potential therapeutic, molecular optimization approaches were limited to semi-synthetic approaches based onmodification of the already existing natural product, severely limiting exploration of potential chemical space.However, we hypothesize based on the availability of modern total synthetic approaches that the streptothricinscaffold can be modified to optimize its properties and develop a much needed therapeutic with activity againstAcinetobacter and other resistant Gram-negative organisms. Preliminary data is presented that shows selectivityfor prokaryotic ribosomes, rapid bactericidal killing, extended in vitro activity spectrum against A. baumannii, andefficacy against A. baumannii in a murine thigh infection model. Furthermore, support for a total convergentsynthetic strategy is presented, which for the first time will allow full exploration of the streptothricin scaffold.Based on these compelling preliminary data and streptothricin's intrinsic antimicrobial activity, two specific goalswill be pursued. The first is to perform structure-activity relationship studies to identify derivatives withsignificantly enhanced prokaryotic selectivity and nonsusceptibility to streptothricin acetyltransferase-basedinactivation, while maintaining activity spectrum and potency. Additional properties will also be examined andaddressed where possible, such as Gram-negative bacterial penetrance, efflux, and metabolic stability. Thesecond goal will be to characterize the ability of streptothricin and analogues to treat XDR Acinetobacter infectionin a murine thigh infection model. Experiments will also specifically examine and define whole animal toxicitiesand iterate back into the medicinal chemistry optimization plan with the long-term goal of developing safe andeffective therapy. The near-term goal of this two-year R21 proposal is to determine the tractability of thestreptothricin scaffold for further medicinal chemistry exploration and to identify several advanced candidates forfurther exploration.