Project no.: S-MIP-25-21
Antimicrobial resistance (AMR) in Pseudomonas aeruginosa (P.a) is a critical global health concern, driven by high mutation rates and stress-induced SOS signaling via the RecA/LexA pathway. This project proposes targeting bacterial evolvability by inhibiting this conserved DNAdamage response. In collaboration with U.S. and Italian partners, we identifi ed compound A12, a small molecule that binds RecA anddisrupts LexA autocleavage, eff ectively blocking SOS activation at low micromolar concentrations. In Aim 1, we will characterize A12–RecA/LexA interactions via in silico modeling and identify conserved binding sites in wild-type and drug-resistant strains. In Aim 2, we willdesign and synthesize A12 analogs using rational drug design and retrosynthetic approaches. In Aim 3, lead compounds will be evaluatedfor RecA/LexA inhibition, cytotoxicity, and suppression of virulence and resistance in vitro and in vivo. In Aim 4, structural studies using X-ray crystallography will elucidate RecA–ligand interactions to guide further optimization. This anti-evolution strategy off ers a novel adjunct tocurrent antibiotics, potentially extending their effi cacy while reducing resistance emergence in P. aeruginosa and other pathogens.
Project funding:
Research Council of Lithuania, Projects carried out by researchers’ teams
Project results:
Planned deliverables include:
1. Peer-reviewed articles (3–4 total):
Objective-based publications:
1. Design and biological evaluation of novel LexA/RecA inhibitors – targeting
Medicinal Chemistry or Antimicrobial Agents and Chemotherapy (Q1).
2. Structural characterization of bacterial SOS pathway targets – targeting
Journal of Structural Biology or Nature Structural & Molecular Biology (Q1).
3. SOS suppression as a novel strategy to prevent resistance emergence
– targeting Nature Communications or PLOS Pathogens (Q1).
All manuscripts will be submitted to Q1 international journals indexed in WoS/Scopus.
Conference presentations – (4–6 total).
Period of project implementation: 2025-11-03 - 2028-10-31
Project coordinator: Kaunas University of Technology
Project partners: Pontificia Universidad Católica de Valparaiso, Center for Discovery and Innovation
