TY - JOUR

T1 - Auranofin inhibits virulence pathways in Pseudomonas aeruginosa

AU - Yam, Joey Kuok Hoong

AU - Tan, Leon Zhen Wei

AU - Hong, Ziyan

AU - Salido, May Margarette Santillan

AU - Woo, Bau Yi

AU - Yong, Adeline Mei Hui

AU - Tan, Casandra Ai Zhu

AU - Li, Sam Fong Yau

AU - Yang, Liang

AU - Givskov, Michael

AU - Chng, Shu Sin

N1 - Funding Information: We thank Young-Tae Chang (POSTECH) for allowing access to small molecule libraries used in this study. We acknowledge Song Lin Chua (SCELSE, The Hong Kong Polytechnic University) for his help in processing and submitting our samples for proteomics analysis. We thank Yingying Li (SCELSE, NTU LKCMedicine) for her guidance in RT-PCR experiments. Funding Information: This research was supported by the National Research Foundation and the Singapore Ministry of Education under its Research Centre of Excellence Programme, and by the Ministry of Education Academic Research Fund Tier 2 grant (MOE2016-T2-1-104) (to S.-S.C.). M.G., S.-S.C., L.Y., L.Z.W.T., and Z.H. have filed an international patent application (PCT/SG2016/050436, filed 6th September 2016) and granted a US patent (US 10,258,640 B2, dated 16th April 2019) on the work described in this manuscript. Publisher Copyright: © 2023 Elsevier Ltd

PY - 2023

Y1 - 2023

N2 - Pseudomonas aeruginosa is widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to form biofilms, P. aeruginosa infections are challenging to treat. P. aeruginosa employs multiple virulence mechanisms to establish infections, many of which are controlled by the global virulence regulator Vfr. An attractive strategy to combat P. aeruginosa infections is thus the use of anti-virulence compounds. Here, we report the discovery that FDA-approved drug auranofin attenuates virulence pathways in P. aeruginosa, including quorum sensing (QS) and Type IV pili (TFP). We show that auranofin acts via multiple targets, one of which being Vfr. Consistent with inhibition of QS and TFP expression, we show that auranofin attenuates biofilm maturation, and when used in combination with colistin, displays strong synergy in eradicating P. aeruginosa biofilms. Auranofin may have immediate applications as an anti-virulence drug against P. aeruginosa infections.

AB - Pseudomonas aeruginosa is widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to form biofilms, P. aeruginosa infections are challenging to treat. P. aeruginosa employs multiple virulence mechanisms to establish infections, many of which are controlled by the global virulence regulator Vfr. An attractive strategy to combat P. aeruginosa infections is thus the use of anti-virulence compounds. Here, we report the discovery that FDA-approved drug auranofin attenuates virulence pathways in P. aeruginosa, including quorum sensing (QS) and Type IV pili (TFP). We show that auranofin acts via multiple targets, one of which being Vfr. Consistent with inhibition of QS and TFP expression, we show that auranofin attenuates biofilm maturation, and when used in combination with colistin, displays strong synergy in eradicating P. aeruginosa biofilms. Auranofin may have immediate applications as an anti-virulence drug against P. aeruginosa infections.

KW - Auranofin

KW - Colistin

KW - Gold(I)

KW - Infection

KW - Motility

KW - Pseudomonas aeruginosa

KW - Quorum sensing

KW - Synergy

KW - Thiophilic

KW - Virulence

U2 - 10.1016/j.bmc.2023.117167

DO - 10.1016/j.bmc.2023.117167

M3 - Journal article

C2 - 36682225

AN - SCOPUS:85146648255

VL - 79

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

M1 - 117167

ER -