Synthesis and Chemical Biology of Thiopeptide Antibiotics
Biography Overview PROJECT SUMMARY/ABSTRACT Antibiotics have transformed the human health and disease landscape. However, the use and misuse of such antimicrobial drugs accelerate the emergence of bacterial strains resistant against antibiotics, so that standard treatment options eventually become ineffective. In light of these critical needs, thiopeptides have emerged as a promising platform for the discovery of new therapeutic leads. In Aim 1, we will develop and optimize the preparation of 26-membered thiopeptides by inventing a new cyclodehydration methods to facilitate the synthetic campaign. The methods established in this aim will be validated in the context of representative azole/azoline-containing antimicrobial peptides. In Aim 2, we will optimize a streamlined synthesis of 35-membered thiopeptides by integrating Mo-catalyzed cyclodehydrations and site- selective Dha mutations. These findings will unlock the translational potential of a previously unexplored class of potent antibiotics. In Aim 3, we will develop an automated platform for rational thiopeptide design and modifications, and integrate it with microbiological, biophysical, and computational studies to generate promising leads suitable for pre-clinical and clinical investigations. Successful realization of the abovementioned aims will establish innovative tools for the synthesis of thiopeptides and other bioactive macrocyclic peptides. Because of the importance of azol(in)es as the key structural elements in bioactive natural products of biomedical relevance, the discoveries of this study will have a transformative impact on the development of new therapies.
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