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Tuesday, April 24 • 12:00pm - 1:30pm
Synthesis And Antibiotic Evaluation Of Bedaquiline Analogs That Target ATP Synthase In Escherichia coli

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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. Gram-negative bacteria, such as Escherichia coli (E. coli), are representative of this need as their treatability is particularly difficult due to the addition of a thick outer membrane and high levels of molecular machinery such as drug efflux pumps to diminish antibacterial activity. 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 target specifically target ATP synthase in E. coli. Using electrophilic aromatic substitutions reactions, a variety of C2 BDQ analogs are being synthesized and evaluated for ATP synthase inhibition using a ATP-driven H+ pumping assay in inside-out membrane vesicles. Development of the diarylquinolines class may represent a promising strategy for combating Gram-negative pathogens.


Tuesday April 24, 2018 12:00pm - 1:30pm PDT
Sherrill Center Concourse