Structure-Guided Covalent Design and Biological Evaluation of Glycidamido-Leucinamide Antivirulence Agents Against Pseudomonas aeruginosa.
- 1College of Pharmacy, Shihezi University, Shihezi 832003, China.
- 2College of Pharmacy, Jinan University, Guangzhou 510632, China.
- 3School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
Abstract
Antimicrobial resistance in Pseudomonas aeruginosa has intensified the need for therapies that do not rely solely on bactericidal activity. Antivirulence agents attenuate pathogenic functions and may complement conventional antibiotics. The elastase LasB is a major quorum-sensing (QS)-controlled virulence factor of P. aeruginosa. Starting from the validated N-aryl/α-isobutyl recognition motif of LasB inhibitors, we used an integrated computational workflow combining chemical-space mapping of known LasB inhibitors, focused covalent-library enumeration, and Glu141-directed covalent docking to design glycidamide analogues bearing an epoxide-containing motif. Two compounds were synthesised and characterised, QSI-1 (4-(trifluoromethyl)phenyl) and QSI-2 (4-fluorophenyl), forming a matched molecular pair that differs only at the para substituent. Both compounds inhibited biofilm formation at sub-micromolar concentrations (QSI-1, IC₅₀ = 0.28 μM; QSI-2, IC₅₀ = 0.51 μM) and directly inhibited purified recombinant LasB, with IC₅₀ values of 2.98 μM and 10.20 μM, respectively. Both also preferentially reduced lasB promoter activity relative to the rhlA and pqsA reporters. QSI-1, selected for further evaluation, reduced virulence-factor production and surface-associated motility without measurably inhibiting bacterial growth. QSI-1 enhanced the activity of azithromycin in vitro, and the combination of QSI-1 (25 μM) with azithromycin (0.05 μg/mL) accelerated wound closure and reduced bacterial burden in a murine excisional wound-infection model. QSI-1 showed low cytotoxicity toward mammalian cells at concentrations up to 200 μM. These findings identify QSI-1 and QSI-2 as covalently designed LasB-active antivirulence leads, while direct experimental confirmation of Glu141 covalent modification remains to be established.
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BibTeX
@article{mu2026structureguided,
title = {{Structure-Guided Covalent Design and Biological Evaluation of Glycidamido-Leucinamide Antivirulence Agents Against Pseudomonas aeruginosa.}},
author = {Xiaoqing Mu and Yujing Huang and Haoming Chen and Xiaojie Huang and Congzhen Shen and Shengrong Li and Junxia Zheng},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198465},
url = {https://europepmc.org/article/MED/42883717},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structure-Guided Covalent Design and Biological Evaluation of Glycidamido-Leucinamide Antivirulence Agents Against Pseudomonas aeruginosa.
AU - Xiaoqing Mu
AU - Yujing Huang
AU - Haoming Chen
AU - Xiaojie Huang
AU - Congzhen Shen
AU - Shengrong Li
AU - Junxia Zheng
PY - 2026
DA - 2026/09/23
JO - International journal of molecular sciences
DO - 10.3390/ijms27198465
UR - https://europepmc.org/article/MED/42883717
AB - Antimicrobial resistance in Pseudomonas aeruginosa has intensified the need for therapies that do not rely solely on bactericidal activity. Antivirulence agents attenuate pathogenic functions and may complement conventional antibiotics. The elastase LasB is a major quorum-sensing (QS)-controlled virulence factor of P. aeruginosa. Starting from the validated N-aryl/α-isobutyl recognition motif of LasB inhibitors, we used an integrated computational workflow combining chemical-space mapping of known LasB inhibitors, focused covalent-library enumeration, and Glu141-directed covalent docking to design glycidamide analogues bearing an epoxide-containing motif. Two compounds were synthesised and characterised, QSI-1 (4-(trifluoromethyl)phenyl) and QSI-2 (4-fluorophenyl), forming a matched molecular pair that differs only at the para substituent. Both compounds inhibited biofilm formation at sub-micromolar concentrations (QSI-1, IC₅₀ = 0.28 μM; QSI-2, IC₅₀ = 0.51 μM) and directly inhibited purified recombinant LasB, with IC₅₀ values of 2.98 μM and 10.20 μM, respectively. Both also preferentially reduced lasB promoter activity relative to the rhlA and pqsA reporters. QSI-1, selected for further evaluation, reduced virulence-factor production and surface-associated motility without measurably inhibiting bacterial growth. QSI-1 enhanced the activity of azithromycin in vitro, and the combination of QSI-1 (25 μM) with azithromycin (0.05 μg/mL) accelerated wound closure and reduced bacterial burden in a murine excisional wound-infection model. QSI-1 showed low cytotoxicity toward mammalian cells at concentrations up to 200 μM. These findings identify QSI-1 and QSI-2 as covalently designed LasB-active antivirulence leads, while direct experimental confirmation of Glu141 covalent modification remains to be established.
SN - 1422-0067
ER -