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Targeting Protein Disorder for the Remediation of Antimicrobial Resistance
Jack O' Callaghan1,2,3, Michael P Ryan4, Sarah Hudson2,3,5
1Department of Physics, Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland.
ACS Omega
|January 1, 2025
Summary
Antimicrobial resistance (AMR) is a major global health threat. This study reveals intrinsically disordered proteins (IDPs) as novel drug targets for combating AMR, particularly in E. coli, opening new avenues for antimicrobial drug discovery.
Area of Science:
- Microbiology
- Biochemistry
- Drug Discovery
Background:
- Antimicrobial resistance (AMR) poses a significant global healthcare challenge.
- Intrinsically disordered proteins (IDPs) are established drug targets for cancer and neurodegenerative diseases, but their role in AMR remains unexplored.
- Understanding the molecular basis of AMR is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the potential role of intrinsically disordered proteins (IDPs) in antimicrobial resistance (AMR).
- To identify novel drug targets for combating drug-resistant bacterial infections.
- To explore the link between protein structural disorder and bacterial susceptibility to antibiotics.
Main Methods:
- Mapping predicted disorder profiles of intrinsically disordered proteins (IDPs) onto transcriptomic data of resistant and susceptible E. coli isolates.
- Classifying AMR-relevant IDPs based on their involvement in bacterial stress response and differential expression after antibiotic exposure.
- Performing residue-wise conservation analysis of bacterial IDPs to identify mutations affecting antimicrobial susceptibility.
Main Results:
- A novel link between protein structural disorder and antimicrobial resistance (AMR) in E. coli was identified.
- AMR-relevant IDPs were categorized into two groups: those involved in stress response and those differentially expressed upon antibiotic exposure.
- Mutations within intrinsically disordered regions of bacterial IDPs were found to correlate with significant changes in antimicrobial susceptibility, particularly in ESKAPEE pathogens.
Conclusions:
- The study highlights intrinsically disordered proteins (IDPs) as promising targets for antimicrobial drug discovery.
- Targeting IDPs offers a novel strategy for the remediation of drug-resistant bacterial infections.
- Understanding the functional importance of intrinsic disorder in bacteria is key to developing new therapies against AMR.
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