Targeting Protein Disorder for the Remediation of Antimicrobial Resistance

The remediation of antimicrobial resistance (AMR) is a fundamental challenge for global healthcare. Intrinsically disordered proteins (IDPs) are recognized drug targets for neurodegeneration and cancer but have not been considered to date for AMR. Here, a novel link between structural disorder and AMR is identified by mapping predicted disorder profiles onto existing transcriptomic data for resistant and susceptible <i>E. coli</i> isolates. The AMR-relevant IDPs fall into two distinct classes, those involved in the bacterial stress response and those differentially expressed between resistant and susceptible strains following antibiotic exposure. A residue-wise conservation analysis of relevant bacterial IDPs identified mutations within intrinsically disordered regions that correlate with pronounced changes in antimicrobial susceptibility, providing valuable insight into the functional importance of bacterial intrinsic disorder in the ESKAPEE pathogens. The identification of susceptibility-inducing IDPs in <i>E. coli</i> highlights the potential of disorder-based antimicrobial drug discovery for the remediation of drug-resistant bacterial infections.