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Antifungal Actinomycete Metabolites Discovered in a Differential Cell‐Based Screening Using a Recombinant TOPO1 Deletion Mutant Strain
Author(s) -
Stadler Marc,
Bauch Frank,
Henkel Thomas,
Mühlbauer Andrea,
Müller Hartwig,
Spaltmann Frank,
Weber Karlheinz
Publication year - 2001
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(200105)334:5<143::aid-ardp143>3.0.co;2-b
Subject(s) - mutant , strain (injury) , mycelium , enzyme , yeast , recombinant dna , chemistry , natural product , biochemistry , actinomycetales , cell culture , enzyme inhibitor , biology , microbiology and biotechnology , streptomyces , bacteria , gene , botany , genetics , anatomy
In the course of a natural product screening for inhibitors of fungal topoisomerase 1 (TOPO 1), extracts from the actinomycete strains WS 1410 and BS 1465 exhibited promising activities. Bioguided fractionation of the culture broth by preparative HPLC methods yielded the collismycins A ( 1 ) and B ( 2 ) as active principles of strain WS 1410. Out of the mycelial extracts of strain BS 1465 the bioactive new natural products, cyclo‐homononactic acid ( 3 ) and cyclo‐nonactic acid ( 5 ) and the structurally related but inactive homononactic acid ( 4 ), were isolated. Both collismycin isomers inhibited the recombinant yeast strains ScAL 141 and ScAL 143 (TOPO 1 deletion mutant) in a non‐specific manner with an MIC in the range of 2 μg/ml. The novel cyclo‐homononactic acid ( 3 ) and cyclo‐nonactic acid ( 5 ) showed higher selectivity towards the wild type strain (MIC = 2 μg/ml as compared to 10μmg/ml for the deletion mutant). All compounds obviously address a target other than TOPO 1 since they do not exhibit activities in a concurrent TOPO 1 enzyme assay.