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US 2019/0093141 A1Published application
Biosynthesis of everninomicin analogs in micromonospora carbonacea var aurantiaca
AssigneeVanderbilt University
InventorsBrian O. BACHMANN, Emilianne M. LIMBRICK, Kasia DEREWACZ
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Abstract
Disclosed are methods of preparing everninomicin analogs by genetic alteration of Micromonospora carbonacea. Everninomicin analogs prepared by these methods and methods of using these analogs to treat infections are also disclosed.
Claims18
-32. (canceled)
A method for producing an everninomicin congener, comprising:
- culturing in a fermentor a Micromonospora carbonacea var. aurantiaca bacterium in a production medium to thereby produce a fermentation culture;
- obtaining from the fermentation culture an extract containing the everninomicin congener;
- and isolating and purifying the everninomicin congener from the fermentation culture extract.
A method for producing an everninomicin congener, comprising:
- culturing in a fermentor a Micromonospora carbonacea bacterium in a production medium to thereby produce a fermentation culture, wherein the bacterium comprises one or more mutations in a gene of the evd gene cluster;
- obtaining from the fermentation culture an extract containing the everninomicin congener;
- and isolating and purifying the everninomicin congener from the fermentation culture extract.
The method of claim 355, wherein the bacterium has altered or deleted O-methyltransferase, C-methyltransferase, and/or nitrososynthase activity.
The method of claim 355, wherein the bacterium comprising one or more mutations in a gene selected from the group consisting of evdM2, evdM3, evdN1, and evdO1.
The method of claim 355, wherein the bacterium comprises Micromonospora carbonacea var. aurantiaca.
A method of transforming Micromonospora, comprising:
- a. contacting one side of a membrane with a conjugation composition comprising a donor bacterium and a recipient Micromonospora bacterium, wherein the membrane is able to be penetrated by Micromonospora mycelia but not the donor bacterium;
- b. incubating the composition for a time and temperature sufficient to grow colonies of Micromonospora which penetrate the membrane;
- and
- c. removing the membrane and donor bacterium, thereby leaving the transformed Micromonospora.
1 more element
A compound having the structure:
- wherein
- R4 is H, OH, CH3, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- R5-R6 are each, individually, H, OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- R7 is H, CH3, CH2OH, C(O)R12, substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- or orsellinyl;
- R8 is H, OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- R9 is H, OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- each R11 is, independently, H, OMe, C1-C6 alkyl, optionally substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol, or a 1-20 atom linker bound to rosaramicin;
- and
- R12 is C1-C6 alkyl, optionally substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol,
- or a pharmaceutically acceptable salt thereof, wherein the compound is not
8 more elements
A compound having the structure:
- wherein
- R3 is H, OH, OCH3, CH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol
- R5 is H, OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- R6 is H, OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- or orsellinyl;
- R7 is H, OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- R8 is OH, OCH3, CH2OH, CHO, CO2H, CO2R12, C(O)R12, or substituted C1-C6 alkyl that is substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol;
- R11 is H, OMe, NH2, NO2, NOH, C1-C6 alkyl, optionally substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol, or a 1-20 atom linker bound to rosaramicin;
- and
- R12 is C1-C6 alkyl, optionally substituted with alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, azido, carboxylic acid, cyano, halide, hydroxy, nitro, sulfonyl, or thiol,
- or a pharmaceutically acceptable salt thereof.
8 more elements
A compound chosen from one of the following structures:
- where R5 is H, OH, or OCH3.
Dependencies are inferred from the claim text.