The emergence of bacterial strains presenting resistance to most antibiotic treatments, including the most recently approved on the market, is now a widespread concern and identified as one of the major healthcare issues of the next decade. The World Health Organization characterized this phenomenon as one of the three greatest threats to human health. Antimicrobial resistance has become a major threat to human health across the globe, resulting in ≈25,000 deaths per year in developed regions of the world such as Europe with associated costs of > $2 billion in healthcare expenses and productivity. In the United States of America (USA) alone, the Center for Disease Control and Prevention (CDC) reported more than 2 million infections annually by antimicrobial resistant pathogenic strains resulting in another ≈25,000 deaths. The toll on developing countries is likely to be even higher.
The current struggle in the antibiotic pipeline with the shortage of new efficient antibacterial drugs not only requires the investigation of novel scaffolds but also the validation of new antimicrobial targets. One suggested approach is to inhibit the virulence system in bacteria to reduce selective pressure compared with targeting pathways essential for survival, hence potentially leading to a diminished mutation rate towards drug resistance. Additionally, by specifically targeting virulence pathways such a drug might not affect the host endogenous microbiota hence limiting side effects. Disulfide bond forming proteins (Dsb) have been highlighted as a key target in this endeavor against pathogenic Gram- negative bacteria.
The process of oxidative folding, i.e. the catalysis of protein folding through disulfide bond formation, has been detected in most pathogenic members of the Enterobacteriaceae family and in other Gram-negative pathogenic species. Our goal is to characterize Dsb proteins from a broad range of pathogenic strains through X-ray crystallography and to design inhibitors using rational structural drug design.