Adenylation Inhibitors

Recent evidence suggests that natural products are much more than simply agents of "microbial warfare" and actually play critical roles in bacterial pathogenesis and communication. In particular, non-ribosomal peptide (NRP) natural products have been identified as key players in bacterial iron uptake, biofilm formation, and commensalism. Thus, small molecule inhibition of NRP biosynthesis provides a powerful means to study the biological roles of these natural products and a potential avenue to develop novel antibiotics. Detailed mechanistic insights into NRP biosynthesis, developed primarily from the perspectives of fundamental interest and engineered biosynthesis, can be leveraged to design such inhibitors.

In collaboration with Prof. Luis E. N. Quadri at Cornell–Weill Medical College, we have developed a number of small molecule inhibitors of NRP biosynthesis using natural product-inspired mechanism- and structure-based design. These compounds target enzymes that catalyze key adenylation reactions in the biosyntheses of iron-chelating siderophores and mycobacterial phenolic glycolipids. We are now advancing these compounds toward preclinical evaluation in animal infection models with Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, the etiologic agent of the plague.