Amphotericin B plays a critical role in the clinical treatment of life threatening systemic fungal infections. It is often considered the gold standard drug of choice in these instances due to its broad spectrum efficacy and the lack of alternatives. However, amphotericin B is also well known for its severe and potentially lethal side effects, including severe nephrotoxicity. Doctors are often left with the difficult choice of balancing the risk of infection with the risk of treatment. A number of strategies have been employed to decrease nephrotoxicity of amphotericin B including, but not limited to, generating glycosylated derivatives at a fixed position to improve solubility, purifying the analogs more stringently, and creating liposomal formulations. These efforts have met with limited success, decreasing toxicity to allow for longer treatment regimens, but also showing considerable different pharmokinetic characteristics compared to standard amphotericin B. Strikingly, medicinal chemistry has not had much success altering the characteristics of amphtotericin B. This is largely true because there are few positions in polyene natural products that are accessible to traditional medicinal chemistry. Still, the few published studies that generate even minor chemical modifications of the core scaffold demonstrate that it is possible to dramatically alter the activity and binding specificity of the compound, supporting the possibility that the antifungal activity of amphoterici B and its toxicity to humans can be decoupled. This would be of enormous value to the infectious disease field. Radiant Genomics believes that the enormous diversity of natural product gene clusters that can be identified through a combination of bioinformatics and next generation sequencing of metagenomes and individual organisms can now be mined to provide candidate natural amphotericin analogs that may have decreased toxicity while maintaining its antifungal properties. These natural analogs will have modifications and structural changes in the core amphotericin B scaffold that are impossible to duplicate through synthetic medical chemistry. Successful production and characterization of a range of natural amphotericin analogs will provide strong proof of concept that the Radiant Genomics natural product discovery platform can allow scientists to quickly interrogate the natural diversity surrounding a targeted natural product, an impossibility using traditional natural product discovery methods, and would revolutionize the field of natural product discovery. A less toxic version of amphotericin B would be primed to become the standard treatment for all systemic fungal infections.
Public Health Relevance Statement:
Public Health Relevance: The discovery of nontoxic polyene antifungals would represent a major advance in the battle against nosocomial fungal infectious disease. This proposal presents a novel, high throughput strategy for the discovery of amphotericin B analogs in the service of discovering new antifungals. We propose to apply our platform to discover and perform first order functional assays with novel amphotericin B analogs in this Phase I proposal.
Project Terms:
Adverse effects; Amphotericin; Amphotericin B; analog; Animal Testing; Antibiotics; Antifungal Agents; Binding (Molecular Function); Bioinformatics; Biological Assay; Biological Factors; Candida albicans; Characteristics; Chemicals; Chemistry; Clinical Treatment; Communicable Diseases; comparative; Crude Extracts; Cryptococcus neoformans; design; Drug Formulations; drug standard; Equilibrium; expression vector; Gene Cluster; Genetic Recombination; genetic regulatory protein; Genomics; Goals; Gold; Human; improved; In Vitro; in vivo; Individual; Infection; Inhibitory Concentration 50; Killings; Left; Libraries; Life; Liposomes; Measures; Medical; meetings; metagenome; Metagenomics; Methods; Mining; Minor; Modeling; Modification; Mus; Mycoses; nephrotoxicity; next generation sequencing; novel; Organism; overexpression; pathogen; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Polyenes; Positioning Attribute; Production; Property; public health relevance; Publishing; research study; Risk; Role; scaffold; Scientist; screening; Services; Small Business Innovation Research Grant; Soil; Solubility; Specificity; standard care; Streptomyces; success; Testing; Toxic effect; Toxicity Tests; Transcription Coactivator; Treatment Protocols; vector
