Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent

Rachel Cochrane, Randy Sanichar, Gareth Lambkin, Bela Reiz, Wei Xu, Yi Tang, John Vederas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

The antimalarial agent cladosporin is a nanomolar inhibitor of the Plasmodium falciparum lysyl‐tRNA synthetase, and exhibits activity against both blood‐ and liver‐stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it is biosynthesized by a highly reducing (HR) and a non‐reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism and subsequent heterologous expression of these enzymes in Saccharomyces cerevisiae produced cladosporin, confirming the identity of the putative gene cluster. Incorporation of a pentaketide intermediate analogue indicated a 5+3 assembly by the HR PKS Cla2 and the NR PKS Cla3 during cladosporin biosynthesis. Advanced‐intermediate analogues were synthesized and incorporated by Cla3 to furnish new cladosporin analogues. A putative lysyl‐tRNA synthetase resistance gene was identified in the cladosporin gene cluster. Analysis of the active site emphasizes key structural features thought to be important in resistance to cladosporin.
Original languageEnglish
Pages (from-to)664
Number of pages668
JournalAngewandte Chemie International Edition
Volume55
DOIs
Publication statusPublished - 24 Nov 2015

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