2. Academic Validation
  3. A thiadiazolylidene-morpholine compound inhibits Pseudomonas aeruginosa by destabilizing the thiamine monophosphate kinase thiL

A thiadiazolylidene-morpholine compound inhibits Pseudomonas aeruginosa by destabilizing the thiamine monophosphate kinase thiL

  • J Biol Chem. 2026 Jun;302(6):113112. doi: 10.1016/j.jbc.2026.113112.
Yingying Li 1,  Jianqing Lin 2,  Zara Chung 2,  Benny Ken Yee Yeo 1,  Julien Lescar 3,  Kevin Pethe 4
Affiliations

Affiliations

  • 1 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
  • 2 NTU Institute of Structural Biology, Nanyang Technological University, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.
  • 3 NTU Institute of Structural Biology, Nanyang Technological University, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Centre, Singapore. Electronic address: [email protected].
  • 4 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Centre, Singapore; Singapore Centre for Environmental Life Sciences and Engineering (SCELSE), Singapore; Ineos Oxford Institute for Antimicrobial Research (IOI), Department of Biology, University of Oxford, Oxford, UK. Electronic address: [email protected].
PMID: 42103215 DOI: 10.1016/j.jbc.2026.113112
Abstract

Pseudomonas aeruginosa, an opportunistic gram-negative pathogen, poses a growing threat in healthcare-associated infections. Its intrinsic resistance and acquisition of carbapenemases have driven widespread multidrug resistance and severely limited treatment options. P. aeruginosa causes life-threatening infections including ventilator-associated pneumonia, bloodstream infections, complicated urinary tract infections, and chronic lung disease in cystic fibrosis. We identified and validated thiL, encoding thiamine monophosphate kinase, as a critical metabolic vulnerability and promising Antibacterial target. ThiL deletion abolished virulence in murine lung and wound models and rendered bacteria incapable of survival without a supraphysiological level of thiamine pyrophosphate. A screen of 1231 kinase inhibitors identified VP3.15 as the first specific ThiL inhibitor with Antibacterial potency. Mechanistic studies showed VP3.15 destabilizes ThiL, promoting protein unfolding and functional loss. These results establish ThiL as a druggable target and highlight metabolic dependencies as a therapeutic opportunity against multidrug-resistant P. aeruginosa.

Keywords

Pseudomonas aeruginosa; antibacterial inhibitor; metabolic vulnerability; protein destabilization; thiamine monophosphate kinase (ThiL).

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