Antifungal actinomycete metabolites discovered in a differential cell-based screening using a recombinant TOPO1 deletion mutant strain.
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 micrograms/ml. The novel cyclo-homononactic acid (3) and cyclo-nonactic acid (5) showed higher selectivity towards the wild type strain (MIC = 2 micrograms/ml as compared to 10 micrograms/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.
Stadler
M
M
Bayer-AG, Pharma Research Center Wuppertal, Life Science Center Natural Products, P.O.B. 10 17 09, D-42096 Wuppertal, Germany. marc.stadler.MS@bayer-ag.de
Bauch
F
F
Henkel
T
T
Mühlbauer
A
A
Müller
H
H
Spaltmann
F
F
Weber
K
K
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D000192:Actinomycetales / Q000737:chemistry*; D000935:Antifungal Agents / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D059004:Topoisomerase I Inhibitors
D000935:Antifungal Agents; D002264:Carboxylic Acids; D059004:Topoisomerase I Inhibitors; C089907:collismycin A; C089908:collismycin B; D015082:2,2'-Dipyridyl; D004264:DNA Topoisomerases, Type I