This invention allows the engineering of semi-synthetic lantibiotics to a much larger extent than using typically practiced in vivo methods. The method is the...
This invention allows the engineering of semi-synthetic lantibiotics to a much larger extent than using typically practiced in vivo methods. The method is the first in vitro reconstruction lantibiotic photosynthesis and introduces non-proteinogenic amino acids.
Lantibiotics are peptide-based compounds produced by bacteria that live on lactic acid. They are used as natural antibiotic food preservatives as an alternative to chemical reagents and have been used for half a century without any significant signs of lantibiotic-resistant bacteria popping up.
Researchers at the University of Illinois have isolated and purified the LctM enzyme, responsible for synthesis of lacticin 481. This approach, the first in vitro reconstruction of lantibiotic biosynthesis, allows for lantibiotic engineering and opens the door to possible generations of new lantibiotics with greatly increased yields and improved activities.
Applications
Food preservation
Industrial enzyme production
Bioengineering of novel lantibiotics
Benefits
Greater Production Flexibility: In vitro methodology allows for lacticin 481 production using semi-synthetic substrates.
Avoids Complications of In Vivo Production: In vitro methods avoid product cytotoxicity, degradation and bypasses many of the In vivo regualtory complications.
Better Resistance Profile: Lantibiotics have been used for half a century in more than 40 countries without any significant signs of lantibiotic-resistant bacteria appearing.
More Possibilities: The method works well with combinatorial techniques, increasing the number of substrates that can be used in production of lacticin 481. In addition, isolation of the LctM enzyme allows for more efficient synthesis with greater structural and functional tolerance of the biosynthetic pathway.
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.
Details
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.
Applications
Currently, the compounds are being evaluated for their ability to act as:
Broad spectrum anti-infectives
Cytotoxic cancer drugs
Other compounds produced using similar chemistry may have a wide range of medical applications
Benefits
Novel Mechanism: These compounds act on the isoprenoid pathway using a chemical interaction that has not been previously described.
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.
Professors Keith Jarosinski and Ying Fang at the University of Illinois Urbana-Champaign have generated a panel of antibodies that target and bind an uncharacterized...
Professors Keith Jarosinski and Ying Fang at the University of Illinois Urbana-Champaign have generated a panel of antibodies that target and bind an uncharacterized receptor protein involved in chicken herpes virus infection, a common disease in livestock chickens
Antibodies can be used to research chicken herpes virus transmission and infection, as well as to investigate the role of the CR1L receptor protein in viral infection
