New anti-infectives are required now more than ever as resistance to existing drugs increases in prevalence. Enzymes unique to bacteria or parasites are potential...
New anti-infectives are required now more than ever as resistance to existing drugs increases in prevalence. Enzymes unique to bacteria or parasites are potential drug targets with minimal side effects because they are not present in humans. One such source of potential drug targets is the isoprenoid biosynthesis pathway. Many pathogenic bacteria and malaria parasites use isoprenoids in their cell walls, to protect against the human immune system, and for other functions. This pathway is not present in humans and thus is an excellent target for new anti-infective drugs. Scientists from the University of Illinois at Urbana-Champaigns Departments of Chemistry and Biophysics have identified a class of novel chemical entities that are capable of inhibiting two key enzymes, GcpE and LytB, in the isoprenoid biosynthesis pathway. These compounds are able to inhibit the isoprenoid biosynthetic pathway at concentrations far lower than any other known inhibitors and have the potential to treat a wide-range of infectious disease caused by both bacteria and malarial parasites. In addition, it may be possible to use these compounds for the treatment of cancers, via immune system activation.
This invention includes a class of novel chemical entities composed of similar geometries and bonds. They inhibit through a unique organometallicinteraction that has not been previously described.
Currently, the compounds are being evaluated for their ability to act as:
Continued work on these compounds is designed to identify new applications of this interaction, beyond anti-infectives.
Dr. Paul Hergenrother fhas developed a new series of broad spectrum fusidic acid derivatives. Designed using two distinct methodologies, these fusidic acid derivatives...
Dr. Paul Hergenrother fhas developed a new series of broad spectrum fusidic acid derivatives. Designed using two distinct methodologies, these fusidic acid derivatives feature unique side chains and demonstrate improved MIC values when compared with fusidic acid. One series of derivatives displays antibiotic activity against Gram-negative ESKAPE pathogens, including in clinical isolates of P. aeruginosa. The prodrug displays low toxicity in mammalian cells and human serum experiments suggest that it is less protein bound than Fusidic Acid. A second series of derivatives displays potent activity against clinical isolates of Staphylococcus aureus and Enterococcus faecium and an improved resistance profile in vitro and in vivo when compared to fusidic acid. Additionally, these derivatives display in vivo efficacy against an FA-resistant strain of Staphylococcus aureus in a mouse infection model.