The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms.
In a screening of natural products with antifungal activity derived from endophytic fungi, we detected a potent activity in a culture belonging to the form-genus Hormonema, isolated from leaves of Juniperus communis. The compound is a new triterpene glycoside, showing an antifungal activity highly potent in vitro against Candida and Aspergillus and with moderate efficacy in an in vivo mouse model of disseminated candidiasis. The agent is especially interesting since its antifungal spectrum and its effect on morphology of Aspergillus fumigatus is comparable to that of the glucan synthase inhibitor pneumocandin B,,, the natural precursor of the clinical candidate MK-0991 (caspofungin acetate). An additional search for other Hormonema isolates producing improved titers or derivatives resulted in the isolation of two more strains recovered from the same plant host showing identical activity. The producing isolates were compared with other non-producing Hormonema strains by DNA fingerprinting and sequencing of the rDNA internal transcribed spacers. Comparison of rDNA sequences with other fungal species suggests that the producing fungus could be an undetermined Kabatina species. Kabatina is a coelomycetous genus whose members are known to produce Hormonema-like states in culture.
Peláez
F
F
Centro de Investigación Básica - Natural Products Drug Discovery, Merck Research Laboratories, Merck, Sharp and Dohme de España, Madrid, Spain. fernando_pelaez@merck.com
Cabello
A
A
Platas
G
G
Díez
M T
MT
González del Val
A
A
Basilio
A
A
Martán
I
I
Vicente
F
F
Bills
G E
GE
Giacobbe
R A
RA
Schwartz
R E
RE
Onish
J C
JC
Meinz
M S
MS
Abruzzo
G K
GK
Flattery
A M
AM
Kong
L
L
Kurtz
M B
MB
D000818:Animals; D000935:Antifungal Agents / Q000302:isolation & purification*; D001230:Aspergillus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D016172:DNA Fingerprinting; D004305:Dose-Response Relationship, Drug; D005658:Fungi / Q000145:classification / Q000378:metabolism*; D006027:Glycosides / Q000302:isolation & purification* / Q000494:pharmacology; D018653:Juniperus / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D016533:Mycological Typing Techniques; D013729:Terpenes / Q000302:isolation & purification* / Q000494:pharmacology; D014315:Triterpenes
D000935:Antifungal Agents; D006027:Glycosides; D013729:Terpenes; D014315:Triterpenes; C421868:enfumafungin