Abstract

Emergence of drug-resistant bacteria represents a high, unmet medical need, and the added lack of antibacterial agents with novel mechanisms of action only compounds this issue. Treatability of Gram-negative bacteria, such as Escherichia coli (E. coli), is particularly difficult due to the addition of a thick outer membrane and high levels of molecular machinery such as drug efflux pumps. Therefore, innovative antibacterial mechanisms of action are greatly needed to combat this issue. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the novel drug, Bedaquiline (BDQ). However, potency of BDQ is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify the differences in the ATP synthase amino acid sequence of each pathogen and synthesize analogs of BDQ that specifically target ATP synthase in E. coli. Using electrophilic aromatic substitution reactions, a variety of C2 BDQ analogs have been synthesized and evaluated for ATP synthase inhibition using an ATP-driven H+ pumping assay in inside-out membrane vesicles. Three of these base analogs, one with a naphthalene substituent, another with a hydroxy, and the other with a N-dimethylaminopropanol, have shown activity toward both E. coli and Staphylococcus aureus within the 100-1000 μg/mL range and have since been further elaborated structurally at the C3 position. Development of the diarylquinolines class may represent a promising strategy for combating Gram-negative pathogens.

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