The rising epidemic due to lack of treatments for drug-resistant gram-negative bacteria call for new advances and approaches to antibiotic discovery. The novel drug, Bedaquiline (BDQ), bypasses regular antibiotic mechanisms of cellular membrane penetration and targets the F-ATP synthase (F-ATPase) of Mycobacteria tuberculosis (M. tb); however, BDQ is specific to M. tb. Analogs of BDQ will be synthesized to determine factors influencing binding affinity to E. coli’s F-ATPase; however, due to the differences in amino acid sequence between it and M. tb at positions 32, 65, and 67, research will be primarily focused there. Synthesis of the base analog structure begins with a methoxy addition, a dimethylamine addition, and a Grignard synthesis. Targeted analogs are those with strong hydrogen bonding at position 65. Position 32 facilitates steric alignment and, therefore, long carbon chains will be added to the α carbon to mimic BDQ but reduce steric hindrance. Antibiotic potential will be assessed through liquid bacterial inhibition assay against a variety of Gram-negative pathogens.
