PROJECT SUMMARY
Sugar mimetics have long been known for their important biological activities. Many of them are currently used
in clinics as antimicrobials (e.g., streptomycin, gentamycin, neomycin), antivirals (e.g., oseltamivir, peramivir,
entecavir), and anti-diabetics (e.g., acarbose, voglibose). Among naturally-occurring sugar mimetics are the
aminocyclopentitols, which contain a five-membered cyclitol unit resembling ribose (ribomimetics). However,
due to their broad-spectrum toxicity and/or low production yield, none has yet been developed for clinical use.
Therefore, addressing these limitations may provide new paths to the exploitation of their full potential as new
drug leads. The long-term goals of this project are to understand the biosynthesis of ribomimetic natural
products and to develop new ribomimetic-based drugs to combat infectious diseases. In this proposal, we will
focus effort on interrogating the biosynthesis of the ribomimetic-containing antibiotic pactamycin and
developing new pactamycin analogs as drug leads against bacteria, viruses, and malarial parasites. Our
preliminary data suggest that formation of the pactamycin core structure involves highly unusual discrete
polyketide synthases, a broad-spectrum glycosyltransferase, and a radical SAM enzyme. We also found that
the tailoring pathway to pactamycin is exceptionally perplexing, due to the activity of numerous promiscuous
tailoring enzymes. Furthermore, we have developed genetic, synthetic, and chemo-enzymatic strategies
(involving a broad-spectrum ketoacyl-ACP synthase (KAS) III-like protein) to produce new pactamycin analogs
and other ribomimetic compounds, some of which have improved biological properties. Here, we propose to: 1)
characterize the coordinate function of discrete PKS proteins and the unusual glycosylation of an acyl carrier
protein (ACP)-bound polyketide intermediate; 2) decipher the mode of formation of the ribomimetic core, which
is predicted to take place via a distinctive biotransformation mediated by radical chemistry; and 3) develop and
test new ribomimetic antibiotics for anti-infective activities. Successful completion of this research will advance
scientific knowledge and technical capability in the field, and will address the current slow pace of progress in
the discovery of new anti-infective drugs, particularly antibacterial, antiviral, and anti-parasitic agents.