About This Project

The synthesis of compounds inspired by the molecules of nature is a proven strategy for discovering new anti-infective compounds. The Kasugamycin family of natural products has clinically relevant antifungal and antibacterial properties. We will use our laboratory's technology to make and test analogues of (+)-Kasugamycin for antifungal and antibacterial activity. We hypothesize that this will create a library of useful "drug-like" Kasugamycin analogues for further development.

Ask the Scientists

What is the context of this research?

Since the commercialization of penicillin, antibiotics have been hailed as “magic bullets”. In recent years, however, the number of bacterial strains resistant to clinically used antibiotics has sharply increased, and the economic burden from this is projected to be ~$159 billion dollars. Thus, the development of antibiotics with new mechanisms of action for the control of pernicious bacterial infections is of vital importance. The main mission of my laboratory at the University of Kansas Department of Medicinal Chemistry is to reduce human morbidity and mortality through innovation in synthetic organic chemistry. In this project, we will synthesize molecules in the Kasugamycin family of aminoglycoside antibiotics with the goal of finding a pre-clinical "hit" compound, which can be evolved in future medicinal chemistry efforts into a clinical trial candidate.

What is the significance of this project?

The first step in drug-discovery is the generation of pre-clinical "hit" compounds that have favorable activity and toxicity profiles and the evolution of these "hits" into lead compounds for clinical trials. The Kasugamycin family of aminoglycosides includes members that have commercially relevant agricultural fungicidal activity and clinically relevant anti-tubercular activity. We aim to use this family of natural products as inspiration for the assembly of a library of simplified analogues that will retain the attractive antibiotic features of the parent compounds but that will be more "drug-like". If successful, this project will allow for access to a diverse collection of antibacterial compounds with distinct modes of action from FDA approved antibiotics. This will complete many important pre-clinical steps towards the development of new clinically relevant antibiotics. The ultimate goal of this research is to reduce the burden of bacterial infections.

What are the goals of the project?

Over the 1-year duration of this project, we will synthesize a library of simplified Kasugamycin analogues (~50 analogues in total) and will evaluate their activity using a suite of in silico, in vitro, and in vivo assays. We are experts in synthetic organic chemistry and will use our "in-house" expertise to synthesize a collection of simplified, structurally modified analogues to improve drug-like properties and lower background cytotoxicity while maintaining the on-target antibacterial activity of the parent compounds. Our plan for these analogues will be guided by function/diversity-oriented synthesis principles and in silico structure-based design. In collaboration with core laboratories at the University of Kansas and at Kansas State University, we will evaluate the antibacterial activity in vitro, and promising analogues will be tested for toxicity in mice.