The Small Business Innovation Research (SBIR) Phase II project aims to develop differentially protected orthogonal lanthionine technology (DPLOT) to synthesize novel antibiotics. Lanthionines are found in nature and have been isolated from a variety of sources. Although amino acids, lanthionines are not components of proteins. They are however, constituents of a group of naturally occurring peptide antibiotics called lantibiotics, which includes nisin (a food preservative), subtilin, epidermin (an anti staphylococcus and streptococcus agent), and ancovenin (an enzyme inhibitor). Due to their mechanism of action, resistance to lantibiotics is uncommon and as such they can be of value for treating antibiotic resistant bacterial infections.
The technology under development would allow the synthesis of novel lantibiotics that may be effective against the growing number of antibiotic resistant bacteria and would expand the therapeutic arsenal available for treating such infections. It would therefore have a profound impact on public health and the control of infectious diseases caused by bacteria.
In this project, the scientific team at Oragenics developed novel methods to synthesize a new antibiotic called Mutacin 1140 (MU1140). This new antibiotic belongs to a class of antibiotics called Lantibiotics. The overall goals were to produce enough MU1140 to enter clinical trials with this novel compound. Although we were ultimately successful in engineering a solid-phase synthesis platform and produce synthetic MU1140, the limitations imposed by this process made impossible the scale-up to the levels that were originally anticipated, and precluded the completion of the pre-clinical and clinical testing of MU1140. Additional development and optimization will be required to further develop a production/ purification process that lowers the cost-of-goods to a commercially-viable range for synthetic MU1140 to be produced as an active pharmaceutical ingredient. These activities are ongoing at Oragenics. Interestingly, the changes that needed to be applied to produce MU1140 synthetically impacted its biological activity in an unanticipated manner. In retrospect, this important finding may potentially allow the design of analogs of MU1140 with a narrower spectrum of activity against infections caused by C. difficile. Overall, the results from this project have profound implications in our ability to design and commercially develop MU1140 (and analogs) and increase the size of the antibiotic pipeline available to treat infections.
