Nonactin, produced by Streptomyces griseus ETH A7796, is a macrotetrolide assembled from nonactic acid. It is an effective inhibitor of drug efflux in multidrug resistant erythroleukemia K562 cells at sub-toxic concentrations and has been shown to possess both antibacterial and antitumor activity. As total synthesis is impractical for the generation of nonactin analogs we have studied precursor-directed biosynthesis as an alternative as it is known that nonactic acid can serve as a nonactin precursor in vivo. To determine the scope of the approach we prepared and evaluated a furan-based nonactic acid derivative, 11. Although no new nonactin analogs were detected when 11 was administered to S. griseus fermentative cultures, a significant inhibition of nonactin biosynthesis was noted (IC 50 ~ 100 μM). Cell mass, nonactic acid production and the generation of other secondary metabolites in the culture were unaffected by 11 demonstrating that 11 selectively inhibited the assembly of nonactin from nonactic acid. While we were unable to generate new nonactin analogs we have discovered, however, a useful inhibitor that we can use to probe the mechanism of nonactin assembly with the ultimate goal of developing more successful precursordirected biosynthesis transformations.Streptomyces griseus subsp. griseus ETH A7796 (DSM40695) makes a series of ionophore antibiotics known as the macrotetrolides (Figure 1). 1 Nonactin, the prototypical macrotetrolide (1) is assembled from two monomers of (-)-nonactic acid and two monomers of (+)-nonactic acid assembled (+)-(-)-(+)-(-) in a head-to-tail manner into a 32-membered macrocycle. Nonactin has both antibiotic and anticancer properties 2 and has been shown to be an inhibitor of drug efflux in multiple drug resistant cancers.3 The natural macrotetrolide homologues produced by S. griseus show a wide range potency with the minimum inhibitory concentration of 1 being an order of magnitude greater than that of dinactin (3) against Staphylococcus aureus and Mycobacterium bovis, a difference that is related to the stability constants of their respective Na + and K + complexes. 1,2,4 Nonactin is far too hydrophobic and insufficiently soluble to be an effective therapeutic. 5 The development of therapeutics based upon nonactin, therefore, will be dependent upon being able to make non-natural analogs in a direct and efficient manner. The total synthesis of nonactin has been achieved by a number of groups 6-9 as has the synthesis of nonactic acid. 10,11 The total synthesis of nonactin analogs is complicated as both enantiomers of nonactic acid, and its analogs, are required as is the sequential construction of a linear tetraester prior to a © 2008 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published ...
We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis.
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