Targeting Protein Disorder for the Remediation of\nAntimicrobial Resistance

The remediation of\nantimicrobial resistance (AMR) is a fundamental\nchallenge for global healthcare. Intrinsically disordered proteins\n(IDPs) are recognized drug targets for neurodegeneration and cancer\nbut have not been considered to date for AMR. Here, a novel link between\nstructural disorder and AMR is identified by mapping predicted disorder\nprofiles onto existing transcriptomic data for resistant and susceptible E. coli isolates. The AMR-relevant IDPs fall into\ntwo distinct classes, those involved in the bacterial stress response\nand those differentially expressed between resistant and susceptible\nstrains following antibiotic exposure. A residue-wise conservation\nanalysis of relevant bacterial IDPs identified mutations within intrinsically\ndisordered regions that correlate with pronounced changes in antimicrobial\nsusceptibility, providing valuable insight into the functional importance\nof bacterial intrinsic disorder in the ESKAPEE pathogens. The identification\nof susceptibility-inducing IDPs in E. coli highlights the potential of disorder-based antimicrobial drug discovery\nfor the remediation of drug-resistant bacterial infections.