Nanaomycin©

1. Discovery, producing organism and structures1-6)
While screening for antibiotics more active against Mycoplasma gallisepticum than against bacteria, nanaomycins A, B, C, D and E were isolated from the culture broth of the actinomycete
strain OS-3966T. Nanaomycin A was found to possess potent inhibitory activity against fungi.
Nanaomycin A inhibited in vitro growth of the human malaria parasite Plasmodium falciparumwith an IC80 value of 33.1 nM7). The total syntheses of nanaomycins have been reported by manygroups. The first total synthesis of nanaomycins A and D was reported by Li et al.8) (See Appendix-I).
HOOOOH

CH3HOO

COOH

HOCH3OR
Nanaomycin A OH
Nanaomycin C NH2HOCH3O

CH3OOO

Streptomyces rosa subsp. notoensis
OS-3966T

CORO

Nanaomycin B

HOO

Nanaomycin DO

O

COOH

OO

Nanaomycin E

2. Physical data (Nanaomycin A)
Orange needles. C16H14O6; mol wt 302.08. Sol. in MeOH, EtOH, CHCl3, EtOAc.
3. Biosynthesis3,9-12)
Nanaomycins are biosynthesized from eight acetate units via “polyketide” and are converted to
D→A→E→B by enzymatic and nonenzymatic systems.
OO
O

CH313COOH X 8HOO

CH3O
O

O

NADH + H+O

NAD+OOOOHOONanaomycin DHOOH

CH3HOCH3OH

O

HOOH

O

CH3O
COOH

OHOOO

HOO

O

NAD(P)H + H++

HOO+ H++ O2CH3O

NAD(P)+ H2O

HOO

O

COOH
O

Nanaomycin A

NAD(P)H + H

CH3+ H+O

HOO

NAD(P)+OH

O

COOH

O

Nanaomycin E

CH3COOH

OH

Nanaomycin B

4. Biological activity1,2,4,14,15)
1) Antimicrobial activity of nanaomycin A1,2,4)Test organism

MIC(µg/ml)*

Bacillus subtilis PCI219
Staphylococcus aureus FDA209P
Escherichia coli NIHJ
Candida albicans
Aspergillus fumigatus IAM 2612
Microsporum gypseum 704
Trichophyton interdigitale
T. mentagrophytes
T. rubrum
T. schroenleini
Mycoplasma gallisepticum KP-13
M. gallisepticum 333P (spiramycin resistant)

7.8
3.9
31.3
31.2
12.5
0.8
1.6
0.8
0.1
0.2
0.05
<0.013*Nutrient agar for bacteria (pH 7.0, 2 days, 37˚C),
Potato-glucose agar for fungi (pH 6.4, 4 days, 27˚C),
Eiken PPLO agar for mycoplasmas (pH 7.8, 8 days, 37˚C)2) Therapeutic effect of nanaomycin A against Trichophyton mentagrophytes infection in guineapigs13)
Macroscopic Discoverys** Animals yielding negative cultures
Treatment*								(number/total)
ErythemaScale
4 days7 days14 days
Untreated
Nanaomycin A, 1%
Nanaomycin A, 2%++++++++

0/12
12/12
12/12

0/12
9/12
8/12

0/12
6/12
7/12

* Treatment began 2 days after infection and was administered once daily for 8 days.
** Macroscopic Discoverys were graded on a basis of – to +++, depending on the degree oferythema, scaling, and hair growth.

3) Mode of action14,15)
The quinone antibiotics, nanaomycins, are reduced by the respiratory chain-linked NADH or flavin dehydrogenase of the organism. The reduced forms of nanaomycins are quickly autooxidized
by molecular oxygen producing O2—. The ability to produce O2— is related to the antimicrobialactivity of nanaomycins.
5. Nanaomycin is commercially available as an antifungal agent for animals.
6. References
1. [74] S. Ōmura et al., J. Antibiot. 27, 363-365 (1974)
2. [96] H. Tanaka et al., J. Antibiot. 28, 860-867 (1975)
3. [97] H. Tanaka et al., J. Antibiot. 28, 868-875 (1975)
4. [100] H. Tanaka et al., J. Antibiot. 28, 925-930 (1975)
5. [109] S. Ōmura et al., J. Chem. Soc., Chem. Commun. 320-321 (1976)
6. [157] M. Kasai et al., J. Antibiot. 32, 442-445 (1979)
7. [730] Y. Tanaka et al,. J. Antibiot. 52, 880-888 (1999)

8.		
9. [184]
10. [211]
11. [212]
12. [251]
13. [197]
14. [196]
15. [247]

T. T. Li et al., J. Am. Chem. Soc. 100, 6263-6265 (1978)
C. Kitao et al., J. Antibiot. 33, 711-716 (1980)
S. Ōmura et al., J. Biochem. 90, 291-293 (1981)
S. Ōmura et al., J. Biochem. 90, 355-362 (1981)
H. Tanaka et al., J. Antibiot. 35, 1565-1570 (1982)
K. Kitaura et al., Jpn. J. Antibiot. 33, 728-732 (1980)
H. Marumo et al., J. Antibiot. 33, 885-890 (1980)
H. Hayashi et al., J. Antibiot. 35, 1078-1085 (1982)