FG08, Novel Antifungal Agent

22 Pages·2013·1.92 MB·English

K20, Novel Antifungal
Aminoglycoside
Cheng-Wei Tom Chang
Department of Chemistry and Biochemistry
Utah State University
January 29, 2013
Research Overview
Funding: NIH, DOT, USTAR
Antibacterial
and companies
NH2
O Antifungal
HO
O HO O H2ONO NH2 SMA therapeutics
(H2X)n Z (H2N)n HO NH2
aminoglycosides
Carbohydrates bacteria
N bacteria
N N
H
O N
H
(HO)n O Anticancer
H
Small molecule
H bacteria
H cyclopamine
O HO
RN O O Antibacterial cancer cells C. elegans
3
Anticancer
O N NH
O
O R O R O Me
N
N
N N
N N X
Natural products
R R
O heterocyclic O mice
greenhouse
COOH
O NH
pradimicin phycocyanobilin
O OHHO H3C CO2HCO2H H3C lignin
H3CO H3C H3C CHH33C
O
O O O NH
AntiOvHirOal OHHO HO O ONHCH3 NH NH N field testing
HO OH Anti-inflammatory Biofuel
Antifungal 2
Library of Synthesized
Aminoglycosides
NH
2
HO O NH2
HO
H N NH2 OH NH2 HO O
HO 2 OO O OH HN NH2 HHOO O NH HO H2NO NH2 HN OH
O H2N 2 H OH HO NH
O O O N O O 2
NH
R O OH (H2N)n OH O 2 O (NH )
2n
neomycin analogs with N-1 AHB (2) pyranmycin with N-1 AHB (5)
kanamycin analogs
with N-1 AHB (6)
NH
2
NH
2 O
HO O NH2 NH NH2
2
HO NH O H2N O
R' H2NOO O 2 OH NH2 HHOO HO2NO O NH2 NH2 OHO O NOH2 HHOO H2NOHO NH2 NH2
(H2N)n OH (NH2)n O
Pyranmycin (>40) kanamycin analogs with
R O OH O (NH )
3',4'-dideoxygenation (8) 2n
neomycin analogs with
various R’ (>30) kanamycin analogs (>40)
( ): number of aminoglycosides synthesized
3
History: Six Years Ago
“Certain classical aminoglycosides like streptomycin,
neomycin B, paromomycin inhibit important crop
pathogenic fungal oomycetes…”
4
Research Model
Synthesis
Production, R&D
Field testing
FDA registration
Marketing
IP & Licensing
Biology, plant
pathology, R&D
5
Chemical Modification Can Change
the Mode of Action
New method for reviving old drug
Turning aminoglycoside from antibacterial to antifungal
Antifungal
Antibacterial NH
NH 2
2
HO O but not antibacterial
HO O but not antifungal I
HO
HO
H N II
2 NH
HO O 2
NH HO
O 2
HO
NH
O 2
NH
O 2
III
O CH
HO 3
OH
O O
HO OH 6” HO 4” C H
3” 8 17
H N 4”
2
FG08
Kanamycin A
6
FG08, Novel Antifungal Agent
S. cerevisiae
S. aureus E. coli Cladosporium
FG08
KanB
Fungi Diseases caused MIC ( µg/mL)
Fusarium oxysporium Wilt disease 7.8
Ulocladium sp. Human allergen 7.8
Pythium irregularis Damping off 15.12
Rhizopus stolonifer Bread mold 31.2
Cladosporium sp Tomato leaf mold 31.25
Botrytis sp. Soft-rot of vegetables and fruits 31.25
Fusarium graminearum Fusarium head blight (barley, wheat, etc) 15.6
Candida albicans Human pathogen 15.6
Phoma sp. Human allergen 31.25
Chang, C.-W. T.; Fosso, M.; Kawasaki, Y.; Shrestha, S.; Bensaci, M. F.; Wang, J.; Evans, C. K.; Takemoto,
J. Y. J. Antibiot. 2010, 63, 667-672. 7
Aminoglycosides: Traditional
Mode of Action
Aminoglycoside
Cell membrane
ATP
ADP
Cell Death
rRNA
normal
truncated
rRNA
rRNA
DNA
Stage 1
Stage 2
8
How Does FG08 Kill Fungi?
Application of Sytox Dye
Sytox Dye
Membrane
Fungi disrupting agents
Green fluorescence indicates membrane disruption.
9
Effect of Octyl (C8) group
C. albicans
NH
2
HO O
I
HO
H N II
2 NH
O 2
HO
NH
O 2
III F. graminearum
O CH
HO 3
O
HO C H
8 17
FG08
Membrane-disrupting
NH2
HO
O O O
NH H
N O
O OH O O OH HN N NH
H H H H H H
N N N N N O HN
HN NH H NH NH O N NH2
O OH O O O H
O O O NH O OH O HO2C OH NH2
O O O HN O
O NH O H H
O HO O OH N N
H O N
HN H N NH NH O H O
O OH
O
Cl
NH HO O Antibacterial syringomycin Antifungal
daptomycin
10