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.
Anthrax disease, caused the by the bacterium Bacillus anthracis, is a major bioterrorism threat. Currently, B. anthracis infections are treated with various broad-...
Anthrax disease, caused the by the bacterium Bacillus anthracis, is a major bioterrorism threat. Currently, B. anthracis infections are treated with various broad-spectrum antibiotics. Antibiotic treatment must be effective at eliminating all B. anthracis, which often requires over 60 days of antibiotic treatment. Consequently, the current method of treatment increases the dangers of multi-drug resistance. Multi-drug resistance arises from horizontal gene transfer of drug-resistant bacteria and has lead to the generation of many harmful infectious diseases including, but not limited to, Vancomycin-resistant enterococcus (VRE) and Methicillin-resistance Staphlococcus aureus (MRSA). Most current treatments of bacterial infections kill off the human intestinal bacterial which has two negative side effects: the "healthy" bacteria serve as a reservoir for antibiotic resistance and keep other pathogens at bay. Prolonged, broad-spectrum antibiotics leave patients at risk for secondary infections that are harder to treat that the primary infection. Therefore, it would be beneficial to develop a treatment for Anthrax that would avoid these potent side effects. Microcins are antibacterial peptides that differ from popular broad-range antibiotics in a variety of ways.
One important difference is that microcins target a narrow spectrum of bacteria. As a result, natural human microbial flora will go undisturbed aiding in decreased side effects. A second important difference is that microcins are less likely to be horizontally transferred due to their narrow target spectrum and complex machinery required for synthesis and export, which is often encoded on multiple genes. This technology describes a set of genes that generates the novel microcin, Plantazolicin that is specific for B. anthracis, which causes anthrax. A gene cluster encoding the synthesis, modification, immunity and export machinery of the thiazole/oxazole-modified microcin, Plantazolicin, was identified from Bacillus amyloliquefaciens FZB42. The microcin producing strain was modified to increase expression of Plantazolicin by 5-fold compared to wild-type.
The unique antimicrobial peptide Plantazolicin can kill B. anthracis. It is produced by a culturable bacterium, which contains a gene cluster containing all enzymes necessary for synthesis and export. Therefore, its benefits are two-fold: Easily produced in the lab and in large quantities Specific against B. anthracis, the human pathogen responsible for Anthrax Specificity minimizes side-effects cause by disruption of symbiotic microbial flora Specificity reduces the threat for development of multi-drug resistance.