Development of amine-containing cleavable antibiotic-adjuvant linkers for the potentiation of antibiotics in Gram-negative bacteria

Aliyah Rao

Chemistry/Biochemistry

Amanda Wolfe

Antibiotic resistance is a growing health concern and can be deemed a global threat; therefore, the need to develop new novel drugs is essential in combating this problem. In addition to the development of novel drugs, on the market drugs can be reactivated and used to overcome resistance mechanisms that are present in Gram-negative bacteria. One resistance mechanism is the inability for antibiotics to permeate the outer membrane (OM),, constructed of negatively charged lipopolysaccharides, leading to reduced drug accumulation within the cell. One solution to combat this is using permeating adjuvants which can passively diffuse the OM and effectively accumulate an antibiotic within the cell, leading to cell death. Although adjuvants cannot kill bacteria themselves, the potential co-dosing mechanisms with previously synthesized antibiotics can be utilized to overcome resistance and reactivate these drugs. Through the evaluation of previous work on pentamidine and the eNTRy rules developed by Hergenrother et al., there is potential for the formation of permeating adjuvants containing nitrogenous groups to be evaluated. From here, a series of adjuvants were developed which retained the same structural backbone of diphenylsuccinamide with alterations to the nitrogenous groups attached. These poly-nitrogenous compounds, when co-dosed in the presence of an antibiotic, had the ability to cross the OM and accumulate within the cell. Further evaluation regarding the ability for a cleavable antibiotic-bisamine adjuvant hybrid is ongoing. Through a carbamate series linker, antibiotic-adjuvant hybrid molecules can be evaluated for increased effectiveness in comparison to co-dosed permeating adjuvants. In addition to a cell death assay, cleavage studies will be implemented to evaluate the stability and cleavage rates of the synthesized antibiotic-bisamine adjuvant hybrid molecules. The results of this study have the potential to provide a new route to synthesizing molecules by overcoming resistance mechanisms through the reactivation of antibiotics.

Jan-9-2024