PT  - JOURNAL ARTICLE
AU  - Coles, Victoria E.
AU  - Darveau, Patrick
AU  - Zhang, Xiong
AU  - Harvey, Hanjeong
AU  - Henriksbo, Brandyn D.
AU  - Yang, Angela
AU  - Schertzer, Jonathan D.
AU  - Magolan, Jakob
AU  - Burrows, Lori L.
TI  - Exploration of BAY 11-7082 as a novel antibiotic
AID  - 10.1101/2021.09.28.462244
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.28.462244
4099  - http://biorxiv.org/content/early/2021/09/29/2021.09.28.462244.short
4100  - http://biorxiv.org/content/early/2021/09/29/2021.09.28.462244.full
AB  - Exposure of the Gram-negative pathogen Pseudomonas aeruginosa to sub-inhibitory concentrations of antibiotics increases formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity. We confirmed that BAY 11-7082 inhibits growth of P. aeruginosa and other priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, we measured the ability of select analogues to reduce IL-1β production in mammalian macrophages, identifying minor differences in the structure-activity relationship for the anti-inflammatory and antibacterial properties of this scaffold. Although we could evolve stably resistant MRSA mutants with cross resistance to BAY 11-7082 and PSPC, their lack of shared mutations suggested that the two molecules could have multiple targets. Finally, we showed that BAY 11-7082 and its analogues potentiate the activity of penicillin G against MRSA, suggesting that this scaffold may serve as an interesting starting point for the development of antibiotic adjuvants. Competing Interest StatementThe authors have declared no competing interest.ARPAntibiotic Resistance Platform;CCCPcarbonyl cyanide m-chlorophenyl hydrazine;DiSC3(5)3,3’-dipropylthiadicarbocyanine iodide;FICIfractional inhibitory concentration index;LBlysogeny broth;MHAMueller-Hinton agar;MHBMueller-Hinton broth;PMFproton motive force;PSPC3-(phenylsulfonyl)-2-pyrazinecarbonitrile;PTPprotein tyrosine phosphatase;TATtwin arginine translocase