Patent AU-2019101637-A4 (AU)
Title: Streptovaricin derivative, and preparation method and use thereof
Inventor: SUN YUHUI
IPC: C12N15/00
Filed: 2019-12-18
Granted: 2020-02-06
Abstract: The present invention discloses a streptovaricin derivative, and a preparation method and use thereof, and relates to the field of streptovaricin preparation. In the present invention, the novel streptovaricin derivatives 1-4 are obtained by conducting single inactivation or deletion of P450 genes (stvP4 and stvP5) of a post-modification system in the streptovaricin biosynthetic gene cluster of the strain respectively by using Streptomyces spectabilis CCTCC M2017417 as a starting strain, and then separating and purifying the crude extracts of fermentation products of the two mutant strains to obtain the novel streptovaricin derivatives 1-4. The novel streptovaricin derivatives of the present invention have good antibacterial effects, may provide a new solution to the problem of antibiotic resistance, and provides a basis for structural modification of streptovaricin antibiotics. H H N -~8 N ~N LOAc 00 0, H I0 HO, COOMe O H OH -OH 28-dehydroxylated Streptovaricin F(1) 6-methoxy-8-hydroxy-24-carboxymethyI -tnrotoStrentovaricineI1(2) ~- 0 HO -- 0 HO OAc HO, K 0I n OAc HO, 0 H 2 0ODH 24 ~OH 6H ~OH OH 24-decarboxylated methyl Streptovaricin G(3) 24-decarboxylated methyl Streptovaricin C(4) a b C CCTCC M2017417 (p (wild-type) ..HindiII V'pst NdeI/4-58 a b971 b CCTCCM2017(P417'0 (wild-type) \HnII 'sV Nd Ill~X Streptovaricin D protoStreptovaricine I AStvP4 __ l CCTCC M2017417 10 15 20 25 30 lime (min) 100 0 OH H 738.31012 [M+HJ' 100 69.26(MH0H]O 0 H N 69.28[MH0+l NH 0 N 2 0o OH OH 0sH 10I OH~ H o..437M+] 10H 0 . OH .45[ H ~~5_ OHHH50 73431250(0.-OH 6 700 80 . 0 700 800 M/Z 100~ ~ ~ ~ ~~~~FG 05HH7245 0 HH76387MH 61-62-12 -20 -100 -50 C4 )4 N - C4 C4 C4J .0 9.5 9.'0 8.5 8.0 7.05 7.0U 605 600 5.5 5.0 4.'5 4.'0 3.'5 3.0 2.'5 2.0 1.5 1.0O 0.'5 0'0 -0.5 -1.0 ft (pm1 FIG 6a -170W -4W0 1.10 2.0 170 19 10 fQ t 10 140 130 1..0 JO lo0 90 40 70 00 51 40 50 2'0 10 U FIG 6b fil-b2A CSY gI 0 FI 6c , 10 -90 :0 6.0 7.5 7.060.0 6.0 5.5 5.0 4.5 4.0 30 3.0 15 2.0 1.5 1.0 0.5 0.0 f2 (ppm) FIG 6d 6111-b'1 -20 -40 -100 -120 -140 * - 160 -10 -200 7.5 71'0 6.5 6.'0 5!5 5!0 4'5 4,'0 3.' 3.0 2.'5 2.0 1: t o 05 0.0 f2 (p FIG 6e -550 -450 -400 -200 0 9.5 1.1 .5 B..1 7. 75 a 05 b00 51 5 0 4. 5 4.0 31 1 0 2. 2.0 15 1.0 .5 0.0 1, -1a il (50M) FIG 7a 02 y -00 -700 -500 -400 -300 20 2 0 05 0! 0 10 10 0U 140 135 1"0 0i 0 9u w 75 00 40 02 0 0 0 FIG 7b 61-62B COSY 8.0~~~~ ~ ~ I. 7. .I. . . . 530252U15100 . f2 (p. FI 7c '7 . /1 1 U1-0~-0 -30 -9D -110 -140 FIG 7d * -50 -100 -120 -140 -200 7.5 7.0 6.5 6,0 5.5 5.0 4.5 4.0 3,5 3.0 215 2.0 1.5 1.0 0.5 0.0 f2 (ppm) FIG 7e r,1-52A-H 44 S & 3-4 S 250 '>Y -~V-240 -21 -220 I 4 210 4 -200 -170 -10 -20 -0 710 y P~l y y 10 C4 - Ili --20 .0 10. 5 10. 0 90'5 9.0 0.'5 0. 70' 7.0 0. 6.0 5.' 5.'0 4.0' 4.'0 3.5 3.'0 2.5 2.'0 L.5 1.0 0.5 0.'0 -0. -1.,0 fl (p.) FIG 8a 51-520-C C4 d d' ' i C 10 1- T -- - - -- I -Y~W100 -1650 -1500 -13500 -1200 -1150 ,5000 -750 -600 -500 -200 20 210 200 190 180 170 160 150 140 130 120 110 100 90 00 7'0 5 50 4'0 30 20 10 0 fl (pp.) FIG 8b 0l/i12 Its 1I 10 9 9 7 4 4 I 0 FIG 8c 51-52A SOC * -10 4 -20 -30 -40 -70 - -0 _100 110 t -120 -1 30 -140 -1 50 -10 0.'5 0.0O 7.5 7.'0 6.5 6.'0 5.5 5.0 4.5 40 32 35' 252'0 1.5 1.0 0.5a 0.'0 -05 f2 19004 FIG 8d 1(0/113 -40 1w 140, FIG 8e 1111=10''Id - -100 -70 -40 j -0 1 -20 100 0 40000700115 0 411 4 0 . 10111 21.9O 85 80 7. . A 55 5. : :0 35 30 25 20 1.5 11 0.0 0:5 0 00 -10 01 00,7 FIG 9a -1200 -1100 -100 -700 -00 * 500 * 400 I-2 -00 20 210 200 190 100Q 170 1I0 150 140 130 120 110 100 90 80 70 00 50 40 3O 2'0 0 U FIG 9b -~-0 -- 4 F9c -40 Al" 70 All, -0 AlAO -140 -150 1. 10 ", AAA 55 5A0 4,5 4 3, 5 0 3l 5 z0 o S 1 0 0. 0,0 -o, FIG 9d 1-720 -30 -90 -110 -- 130 -10 - -170 7 7 170 15 0,0 1. 5,0 4,15 4 0 3.17 3,0 2.17 2,0 1,5 LO 0. 5 130 f2 (pp.) FIG 9e