Deshydroxy Vancomycin Preparation via Multi-Step Chromatography
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Solution Overview
Problem
There is an urgent need for novel antibiotics to treat human diseases, particularly against methicillin-resistant Staphylococcus aureus and Clostridium difficile infections, as existing vancomycin derivatives may lose activity due to structural modifications and variations in fermentation strains.
Innovation Solution
A method for preparing deshydroxy vancomycin through fermentation of Amycolatopsis orientalis, involving the steps of preparing a concentrated solution, separating and purifying using column chromatography with specific mobile phases, and further purification with macroporous adsorption resin chromatography, to obtain a refined filtrate containing vancomycin hydrochloride and deshydroxy vancomycin.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If structural modification is performed on known antibiotic substances to develop new drugs, then novel antibiotics can be obtained, but the modified substances may lose the required antibacterial activity
Solution Approach 1:
The invention changes the chemical structure parameter of vancomycin by removing the hydroxyl group at position 4 to create deshydroxy vancomycin. This specific structural modification maintains the glycopeptide core framework while altering one functional group, thereby achieving novelty while preserving antibacterial activity against MRSA and C. difficile.
2Adaptability or versatility
If multiple derivatives are produced in vancomycin fermentation, then variety of compounds are obtained, but separation and purification becomes complex
Solution Approach 1:
The invention segments the fermentation broth into different components using a multi-step chromatographic process. First, gel chromatography separates proteins and small molecules from the target glycopeptides. Then, ion-exchange chromatography further separates vancomycin from deshydroxy vancomycin based on their charge differences, achieving pure product isolation.
Solution Approach 2:
The invention uses two different chromatographic media as intermediaries: gel chromatography medium for initial separation and ion-exchange chromatography medium for final purification. Each intermediary is selected based on its specific separation mechanism, enabling efficient isolation of the target compound from complex fermentation broth.
3Reliability
If demethyl vancomycin is used as a congeneric drug, then treatment of Clostridium difficile is achieved, but it cannot replace imported vancomycin completely
Solution Approach 1:
The invention uses the domestic strain Amycolatopsis orientalis to naturally produce deshydroxy vancomycin along with vancomycin during fermentation. This self-service approach allows China to produce its own novel vancomycin derivative domestically, achieving both therapeutic efficacy and drug availability independence.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method effectively isolates high-purity deshydroxy vancomycin, maintaining antibacterial activity and avoiding drug resistance, which can be used in treating susceptible bacterial infections and as a pharmaceutical composition.
Implementation Method 1
preparing a concentrated solution containing vancomycin and deshydroxy vancomycin by fermentations of Amycolatopsis orientalis
Implementation Method 2
separating and purifing the concentrated solution to obtain a refined filtrate containing vancomycin hydrochloride and the deshydroxy vancomycin by column chromatography
Implementation Method 3
further separating and purifing the refined filtrate to obtain the deshydroxy vancomycin by chromatography in a macroporous adsorption resin chromatography column
Data Source
Figure 1
AI summary
The present invention provides a deshydroxy vancomycin compound,a method of its preparation and a pharmaceutical composition comprising a pharmaceutically effective amount of the deshydroxy vancomycin and the use of the said composition in the preparation of drugs for the treatment of susceptible bacteria infections. The method includes the following steps: (1) preparing a concentrated vancomycin solution containing the deshydroxy vancomycin by fermentations of Amycolatopsis Orientalis with Deposit No. CGMCCNO.1183; (2) separating and purifing the concentrated vancomycin solution to obtain a refined filtrate of vancomycin hydrochloride containing the deshydroxy vancomycin by column chromatography; and (3) further separating and purifing the refined filtrate to obtain the deshydroxy vancomycin by chromatography. Wherein, separation and purification is processed by column chromatography in a gel chromatography column containing a salt-water mobile phase, separation and purification is processed by chromatography in a macroporous adsorption resin chromatography column containing a buffer-methanol mobile phase.