It is widely recognized that a variety of major diseases, such as Alzheimer’s disease, Huntington’s disease, systemic amyloidosis, cystic fibrosis, type 2 diabetes etc., are characterized by a common molecular origin: the misfolding of specific proteins. These disorders have been termed protein misfolding diseases (PMDs) and the vast majority of them remain incurable. In ProMiDis, I am developing a unified approach for the discovery of potential therapeutics against PMDs. More specifically, I am generating engineered bacterial cells that function as a broadly applicable discovery platform for compounds that rescue the misfolding of PMD-associated proteins (MisPs). These compounds are being selected from libraries of drug-like molecules biosynthesized in engineered bacteria using a technology that allows the facile production of billions of different test molecules. These libraries are then screened in the same bacterial cells that produce them and the rare molecules that rescue MisP misfolding effectively are selected using an ultrahigh-throughput genetic screen. The effect of the selected molecules on MisP folding is then evaluated by biochemical and biophysical methods, while their ability to inhibit MisP-induced pathogenicity is tested in appropriate mammalian cell assays and in established animal models of the associated PMD. The molecules that rescue the misfolding of the target MisPs and antagonize their associated pathogenicity both in vitro and in vivo, will become drug candidates against the corresponding diseases. This procedure is being applied for different MisPs to identify potential therapeutics for at least four major PMDs: Huntington’s disease, cardiotoxic light chain amyloidosis, dialysis-related amyloidosis and retinitis pigmentosa. Successful realization of ProMiDis will provide invaluable therapeutic leads against major diseases and a unified framework for anti-PMD drug discovery.