Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/163407
Title: Pharmacological perturbation of thiamine metabolism sensitizes Pseudomonas aeruginosa to multiple antibacterial agents
Authors: Kim, Hyung Jun
Li, Yingying
Zimmermann, Michael
Lee, Yunmi
Lim, Hui Wen
Tan, Alvin Swee Leong
Choi, Inhee
Ko, Yoonae
Lee, Sangchul
Seo, Jeong Jea
Seo, Mooyoung
Jeon, Hee Kyoung
Cechetto, Jonathan
Yam, Joey Kuok Hoong
Yang, Liang
Sauer, Uwe
Jang, Soojin
Pethe, Kevin
Keywords: Science::Medicine
Issue Date: 2022
Source: Kim, H. J., Li, Y., Zimmermann, M., Lee, Y., Lim, H. W., Tan, A. S. L., Choi, I., Ko, Y., Lee, S., Seo, J. J., Seo, M., Jeon, H. K., Cechetto, J., Yam, J. K. H., Yang, L., Sauer, U., Jang, S. & Pethe, K. (2022). Pharmacological perturbation of thiamine metabolism sensitizes Pseudomonas aeruginosa to multiple antibacterial agents. Cell Chemical Biology, 29(8), 1317-1324.e5. https://dx.doi.org/10.1016/j.chembiol.2022.07.001
Project: MOE2017-T2-1-063
NRF-NRFI06-2020-0004
Journal: Cell Chemical Biology
Abstract: 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.
URI: https://hdl.handle.net/10356/163407
ISSN: 2451-9448
DOI: 10.1016/j.chembiol.2022.07.001
Rights: © 2022 Elsevier Ltd. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles
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