Download Discovery of Novel Phosphonate Natural Products Joel P. Cioni1

Discovery of Novel Phosphonate Natural Products
Joel P. Cioni1 and William W. Metcalf1
Department of Microbiology1 University of Illinois, Urbana-Champaign
Phosphonic and phosphinic acid natural products present a group of reduced phosphoruscontaining compounds with potent and diverse biological activities that have found widespread
use in both medicine and industry. At a time when the discovery of novel therapeutics is
challenged to keep pace with the demand posed by increasingly resistant pathogens and prevalent
disease, we believe that further exploration into the biosynthesis of these particular compounds is
likely to unearth valuable remedies. The Metcalf group has developed a strategy that employs a
gene-targeted approach to exploit the ever-growing wealth of genomic sequence information, thus
allowing identification of organisms with the potential to produce phosphonate compounds, along
with the corresponding biosynthetic genes. While this strategy has been validated by identifying
and cloning previously known phosphonate gene clusters, a novel phosphonate has yet to be
discovered using this approach. My thesis proposal is to isolate a novel phosphonate from a
Streptomycete identified by this method, elucidate its structure and characterize the
corresponding biosynthetic gene cluster. By employing various analytical and separation
techniques my studies have thus far demonstrated the capacity of a Streptomyces strain to produce
multiple phosphonates and also revealed putative structures for some of these metabolites. Future
efforts will focus on elucidating the structure of the remaining intermediates, defining the
minimal set of genes required for their biosynthesis, determining the sequence of enzymatic steps,
and establishing the nature of their bioactivity. Achievement of these goals will validate a genetargeted strategy for natural product phosphonate discovery while expanding our knowledge of
phosphonate biosynthesis.