Acinetobacter baumannii and carbapenem-resistant Enterobacteriaceae are among an emerging class of multidrug-resistant, Gram-negative bacterial pathogens that are often either effectively untreatable or only treatable with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. Streptothricin is an antibiotic that was discovered over 70 years ago. It has an impressive activity spectrum against otherwise resistant Gram-negative pathogens. However, initial concern around toxicities and the availability of alternative antibiotics precluded its development, and it has largely been forgotten. Moreover, in the past, when it was still considered the basis of a potential therapeutic, molecular optimization approaches were limited to semi-synthetic approaches based on modification 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 streptothricin scaffold can be modified to optimize its properties and develop a much needed therapeutic with activity against Acinetobacter and other resistant Gram-negative organisms. Preliminary data is presented that shows selectivity for prokaryotic ribosomes, rapid bactericidal killing, extended in vitro activity spectrum against A. baumannii, and efficacy against A. baumannii in a murine thigh infection model. Furthermore, support for a total convergent synthetic 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 goals will be pursued. The first is to perform structure-activity relationship studies to identify derivatives with significantly enhanced prokaryotic selectivity and nonsusceptibility to streptothricin acetyltransferase-based inactivation, while maintaining activity spectrum and potency. Additional properties will also be examined and addressed where possible, such as Gram-negative bacterial penetrance, efflux, and metabolic stability. The second goal will be to characterize the ability of streptothricin and analogues to treat XDR Acinetobacter infection in a murine thigh infection model. Experiments will also specifically examine and define whole animal toxicities and iterate back into the medicinal chemistry optimization plan with the long-term goal of developing safe and effective therapy. The near-term goal of this two-year R21 proposal is to determine the tractability of the streptothricin scaffold for further medicinal chemistry exploration and to identify several advanced candidates for further exploration.
The emergence of multidrug-resistant Gram-negative bacteria has compromised our ability to treat infections. Studies in this proposal seek to optimize a natural product called strepothricin to provide a new therapy to treat these very problematic pathogens.
