2. Academic Validation
  3. Pharmacological perturbation of thiamine metabolism sensitizes Pseudomonas aeruginosa to multiple antibacterial agents

Pharmacological perturbation of thiamine metabolism sensitizes Pseudomonas aeruginosa to multiple antibacterial agents

  • Cell Chem Biol. 2022 Aug 18;29(8):1317-1324.e5. doi: 10.1016/j.chembiol.2022.07.001.
Hyung Jun Kim 1,  Yingying Li 2,  Michael Zimmermann 3,  Yunmi Lee 1,  Hui Wen Lim 2,  Alvin Swee Leong Tan 2,  Inhee Choi 4,  Yoonae Ko 4,  Sangchul Lee 4,  Jeong Jea Seo 4,  Mooyoung Seo 4,  Hee Kyoung Jeon 5,  Jonathan Cechetto 5,  Joey Kuok Hoong Yam 6,  Liang Yang 6,  Uwe Sauer 3,  Soojin Jang 7,  Kevin Pethe 8
Affiliations

Affiliations

  • 1 Discovery Biology Department, Antibacterial Resistance Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore.
  • 3 Institute of Molecular Systems Biology, Swiss Federal Institute of Technology in Zürich (ETHZ), Zürich, Switzerland.
  • 4 Translation Research Department, Medicinal Chemistry Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 5 Screening Discovery Platform, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 6 School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore.
  • 7 Discovery Biology Department, Antibacterial Resistance Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. Electronic address: [email protected].
  • 8 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore. Electronic address: [email protected].
PMID: 35901793 DOI: 10.1016/j.chembiol.2022.07.001
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.

Keywords

ESKAPE pathogens; antibacterial; antibacterial screening; antimetabolite; auranofin; fluorouracil; oxythiamine; synthetic lethal interactions; vitamin B1.

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