Antimicrobial activity of ergokonin A from Trichoderma longibrachiatum.
OBJECTIVE
Natural fungal products were screened for antifungal compounds. The mode of action of one of the hits found and the taxonomy of the producing organism were analysed.


RESULTS
An extract from a Trichoderma species showed a more potent activity in an agar-based assay against the null mutant fks1::HIS strain than against the wild-type strain, suggesting that it could contain a glucan synthesis inhibitor. The active component was identified as the known compound ergokonin A. The compound exhibited activity against Candida and Aspergillus species, but was inactive against Cryptococcus species. It induced alterations in the hyphal morphology of Aspergillus fumigatus. The identification of the producing isolate was confirmed by sequencing of the rDNA internal transcribed spacers and comparison with the sequences of other Trichoderma species. The analysis showed that the producing fungus had a high homology with other strains classified as Trichoderma longibrachiatum and its teleomorph Hypocrea schweinitzii.


CONCLUSIONS
The antifungal activity spectrum of ergokonin A and the morphology alterations induced on A. fumigatus are consistent with glucan synthesis as the target for ergokonin A. The production of ergokonin A is not uncommon, but is probably restricted to Trichoderma species.


CONCLUSIONS
The discovery that ergokonin A could be an inhibitor of glucan synthesis, having a structure very different to other inhibitors, increases the likelihood that orally active agents with this fungal-specific mode of action may be developed.
Vicente
M F
MF
Centro de Investigación Básica - Natural Products Drug Discovery, Merck Research Laboratories, Merck, Sharp and Dohme de España, Madrid, Spain. francisca_vicente@merck.com
Cabello
A
A
Platas
G
G
Basilio
A
A
Díez
M T
MT
Dreikorn
S
S
Giacobbe
R A
RA
Onishi
J C
JC
Meinz
M
M
Kurtz
M B
MB
Rosenbach
M
M
Thompson
J
J
Abruzzo
G
G
Flattery
A
A
Kong
L
L
Tsipouras
A
A
Wilson
K E
KE
Peláez
F
F
D000818:Animals; D000935:Antifungal Agents / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D021903:DNA, Ribosomal Spacer / Q000235:genetics; D005658:Fungi / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D012340:RNA, Ribosomal, 5.8S / Q000235:genetics; D017422:Sequence Analysis, DNA; D013261:Sterols / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D014242:Trichoderma / Q000145:classification / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D014871:Water Microbiology
D000935:Antifungal Agents; D021903:DNA, Ribosomal Spacer; D012340:RNA, Ribosomal, 5.8S; D013261:Sterols