Title:

Structure and Function of Microbial Natural Product Macrocycles

Abstract:

Microorganisms are talented chemists that produce structurally diverse specialized metabolites (natural products) with ranging biological properties and largely unknown ecological roles.1 These energetically expensive metabolites are thought to play critical roles in environmental adaption of the producing organisms, and have also served as molecular probes of cellular mechanisms of disease and as pharmaceutical lead compounds.2 In collaborations that integrate microbiologists, synthetic chemists, chemical biologists and pharmacologists, we have characterized complex nonpolar macrocycles of polyketide, peptide or hybrid biogenesis from a variety of microbial consortia, including from living stromatolites that occur peritidally in the Eastern Cape of South Africa,3,4 and from insect-pathogenic fungi. LCMS-based untargeted metabolomics approaches in tandem with phylogenetic and metagenomic sequencing were used to guide targeted chromatographic isolation of key natural product macrocycles at microgram scales for structure elucidation using NMR spectroscopy and chemical derivatization. Large lipophilic macrocycles with constrained conformational flexibility5 may be evolutionarily optimized to access and bind proteins at or in membranes. Thus, in collaborative work to characterize cellular function we have focused on expanding the small class of natural product macrocycles known to disrupt cellular proteostasis by binding the Sec61 translocon to modulate protein biogenesis and secretion.6,7