Pharmacological perturbation of thiamine metabolism sensitizes Pseudomonas aeruginosa to multiple antibacterial agents. Issue 8 (18th August 2022)

• Record Type: Journal Article
• Authors: Kim, Hyung Jun; Li, Yingying; Zimmermann, Michael; Lee, Yunmi; Lim, Hui Wen; Leong Tan, Alvin Swee; Choi, Inhee; Ko, Yoonae; Lee, Sangchul; Seo, Jeong Jea; Seo, Mooyoung; Jeon, Hee Kyoung; Cechetto, Jonathan; Hoong Yam, Joey Kuok; Yang, Liang; Sauer, Uwe; Jang, Soojin; Pethe, Kevin
• Is Part Of: Cell chemical biology. Volume 29:Issue 8(2022)
• Page Start: 1317
• Page End: 1324.e5
• Publication Date: 2022-08-18
• Subjects: vitamin B1 -- oxythiamine -- antimetabolite -- antibacterial -- fluorouracil -- auranofin -- synthetic lethal interactions -- antibacterial screening -- ESKAPE pathogens; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.07.001
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: New therapeutic concepts are critically needed for carbapenem-resistant Pseudomonas aeruginosa, an opportunistic pathogen particularly recalcitrant to antibiotics. The screening of around 230, 000 small molecules yielded a very low hit rate of 0.002% after triaging for known antibiotics. The only novel hit that stood out was the antimetabolite oxythiamine. Oxythiamine is a known transketolase inhibitor in eukaryotic cells, but its antibacterial potency has not been reported. Metabolic and transcriptomic analyses indicated that oxythiamine is intracellularly converted to oxythiamine pyrophosphate and subsequently inhibits several vitamin-B1-dependent enzymes, sensitizing the bacteria to several antibiotic and non-antibiotic drugs such as tetracyclines, 5-fluorouracil, and auranofin. The positive interaction between 5-fluorouracil and oxythiamine was confirmed in a murine ocular infection model, indicating relevance during infection. Together, this study revealed a system-level significance of thiamine metabolism perturbation that sensitizes P. aeruginosa to multiple small molecules, a property that could inform on the development of a rational drug combination. Graphical abstract: Highlights: Oxythiamine, an antimetabolite, perturbs vitamin B1 metabolism in P. aeruginosa Perturbation of thiamine metabolism by OTH inhibits P. aeruginosa growth OTH is bioactivated to OTH-PP, interrupting TPP-dependent enzymes in P. aeruginosa OTH sensitizes P. aeruginosa to several antibiotics and non-antibiotics molecules Abstract : Oxythiamine, an antimetabolite, is bioactivated to OTH-PP and perturbs vitamin B1 metabolism, inactivating TPP-dependent enzymes in P. aeruginosa . Kim et al. demonstrate that perturbation of thiamine metabolism inhibits P. aeruginosa growth and sensitizes the bacteria to multiple approved antibacterial agents, providing insights into combinatorial therapeutic options for pseudomonal infections.