Work

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

Year: 2026

Type: article

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.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113112

Authors: Yingying Li, Jianqing Lin, Zara Chung, Benny Ken Yee Yeo, Julien Lescar, Kevin Pethe

Institutions: Nanyang Technological University, Singapore-MIT Alliance for Research and Technology, University of Oxford, Singapore Centre for Environmental Life Sciences Engineering

Language: English

Topic: Bacterial biofilms and quorum sensing

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,430