Repurposing Auranofin Derivatives as Antimicrobials Against Burkholderia

DUSTIN MAYDANIUK; ZISANUR RAHMAN; SILVIA CARDONA; BIN WU; LAURA BELTINA LEÓN; ANDREW HOGAN; MINGDI YAN

Winnipeg, Manitoba, Canadá

Conferencia; 103rd Canadian Chemistry Conference and Exhibition; 2020

Abstract:Antibiotic resistance poses a global threat for treating bacterial infections. Repurposing currentmedications has gained attention recently as an alternative to develop new urgently-neededantibiotics. Auranofin, a medication used to treat rheumatoid arthritis, and its derivatives haveantimicrobial activity, showing the potential of this FDA-approved drug to be repurposed as anantibiotic. Auranofin kills bacterial cells by inhibiting an enzyme essential for cellular redoxhomeostasis, thioredoxin reductase (TrxB), increasing the amount of damaging reactive oxygenspecies in the cell. However, auranofin is inactive against bacteria containing a secondary redoxhomeostasis pathway, such as that involving glutathione reductase (GR). Burkholderiacenocepacia, a multi-drug resistant bacterium responsible for fatal respiratory infection inindividuals with cystic fibrosis, contains the GR protein. Our goal was to test derivatives ofauranofin for activity against B. cenocepacia. We hypothesize that active derivatives must inhibitboth GR and TrxB. Minimum inhibitory concentration testing of 10 derivatives against a diversepanel of 10 Burkholderia clinical isolates showed promising activity for one compound. Time-killexperiments confirmed that the derivatives are bactericidal against both replicating andnonreplicating cells. To validate TrxB as a target, a knockdown mutant was constructed usingCRISPR-interference. The mutant was used in a susceptibility assay to show its hyper-susceptibilityto this compound. Further testing will examine the ability of the derivatives to inhibit TrxB andGR in vitro, and examine the genetic network underlying the susceptibility to auranofin derivatives.Taken together, our work will generate novel antibiotics effective against B. cenocepacia to bringnew hope for individuals living with cystic fibrosis.