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    Process for preparing 6-aminopenicillanic acid
    4.
    发明授权
    Process for preparing 6-aminopenicillanic acid 失效
    制备6-氨基苯甲酸的方法

    公开(公告)号：US4113566A

    公开(公告)日：1978-09-12

    申请号：US745212

    申请日：1976-11-26

    Applicant: James J. Hamsher ,  Merrill Lozanov

    Inventor： James J. Hamsher ,  Merrill Lozanov

    IPC: C12N11/00 ,  A61K31/43 ,  C07D20060101 ,  C07D499/04 ,  C07D499/08 ,  C07D499/42 ,  C07D499/78 ,  C12P20060101 ,  C12P37/00 ,  C12P37/04 ,  C12P37/06 ,  C12D13/06

    CPC classification number: C07D499/42 ,  Y10S435/873

    Abstract: A simple and efficient process for the deacylation of penicillins to 6-aminopenicillanic acid in which an aqueous penicillin solution is rapidly recirculated through a shallow bed comprising particulate immobilized penicillin acylase at 15.degree.-45.degree. C and pH 6.5-9.0 until substantial conversion results.BACKGROUND OF THE INVENTIONThis invention relates to penicillins. More specifically, it relates to the enzymatic deacylation of penicillins to 6-aminopenicillanic acid.6-Aminopenicillanic acid, commonly referred to as 6-APA, is an intermediate in the manufacture of synthetic penicillins and is prepared among other means by the deacylation of penicillins. This conversion has been effected by both chemical and biochemical techniques. The chemical conversion, as exemplified by U.S. Pat. No. 3,499,909, suffers from being a multi-step process requiring energy-intensive low-temperature conditions and specialized equipment. The biochemical conversion utilizes the enzyme penicillin acylase, or penicillin amidase. In U.S. Pat. No. 3,260,653, the enzyme activity is supplied by certain bacteria or bacterial extracts. This approach is not entirely satisfactory for the industrial production of 6-APA since the product stream is contaminated with the enzyme and/or microbial cells, which must then be removed during product recovery, and the enzyme is used only once. The problems of product contamination and poor enzyme utilization are purportedly overcome in U.S. Pat. No. 3,953,291 by the use of immobilized penicillin amidase-producing microbial cells. Such a process using immobilized cells is still characterized by low productivity, however, since in batch operation the process suffers from its non-continuous nature and excessive handling of the immobilized cell material, while in column operation it suffers from poor pH control and less than optimum enzyme utilization.The use of a shallow bed of microbial cell catalyst for the continuous isomerization of glucose to fructose is disclosed in U.S. Pat. Nos. 3,694,314 and 3,817,832. The shallow bed is reportedly employed to minimize the pressure drop through the catalyst, the desired conversion being achieved by passing the aqueous process stream through several beds in series.SUMMARY OF THE INVENTIONIt has now been found that penicillins can be converted to 6-APA in a simple and efficient manner by rapidly recirculating an aqueous penicillin solution through a shallow bed comprising particulate penicillin acylase catalyst under controlled temperature and pH conditions. Accordingly, the present invention entails a process for the enzymatic conversion of a penicillin to 6-APA which comprises recirculating an aqueous solution of the penicillin through a bed up to about 6 cm deep comprising particulate immobilized penicillin acylase catalyst at a flow rate of at least 0.4 bed volume per minute while maintaining the solution at a temperature of from about 15.degree. to 45.degree. C. and a pH from about 6.5 to 9.0 and continuing the recirculation until the penicillin is substantially converted to 6-APA. Preferably the penicillin is potassium penicillin G, the bed has a depth of from about 2 to 3 cm, the particulate catalyst comprises immobilized Proteus rettgeri cells containing the enzyme, the temperature is about 35.degree. to 40.degree. C. and the pH is from about 7.5 to 8.2.DETAILED DESCRIPTION OF THE INVENTIONThe process of the present invention, in rapidly recirculating the process stream through a shallow bed of particulate catalyst, is thus able to optimize the conversion of penicillins to 6-APA since it overcomes the heretofore unsolved problems of pH and flow control associated with continuous column deacylation and of excessive catalyst handling with batch deacylations. The capability of the process to control pH is especially significant since the deacylation generates a carboxylic acid which must be neutralized, the enzyme is optimally active over a narrow pH range and both the reactant and product are sensitive to pH extremes. Since this control is accomplished with a minimum of pressure drop through the bed, the process has the further advantage of utilizing standard process equipment.The process is suitable for the deacylation of any water-soluble penicillin. Representative penicillins include but are not limited to penicillin G (benzylpenicillin), penicillin X (p-hydroxybenzylpenicillin) and penicillin V (phenoxymethylpenicillin). Preferred is penicillin G in the form of the potassium or sodium salt. The concentration of the penicillin substrate in the aqueous solution is not critical and normally varies from about 1 to 20 g/100 ml solution.By particulate immobilized penicillin acylase catalyst is meant the enzyme penicillin acylase, or any penicillin acylase-producing microorganism, entrapped within or attached to or on a water-insoluble particulate matrix of organic or inorganic origin in such a manner as to retain the enzyme's activity. Suitable penicillin acylase-producing microorganisms include those belonging to the general of Proteus, Escherichia, Streptomyces, Nocardia, Micrococcus, Pseudomonas, Alkaligenes and Aerobacter such as disclosed in U.S. Pats. Nos. 3,260,653 and 3,953,291. The common methods employed for such immobilization of enzymes and microbial cells include covalent bonding to the matrix, entrapment within the matrix, physical adsorption on the matrix and cross-linking with a bifunctional reagent to form the matrix. Illustrative of these immobilization techniques are those of U.S. Pats. Nos. 3,645,852, 3,708,397, 3,736,231, 3,779,869, 3,925,157, 3,953,291 and 3,957,580. As indicated by these references, the matrix is typically a polymer or copolymer of such monomers as glycidyl methacrylate methacrylic acid anhydride, acryloylamide, acrylamide, styrene, divinylbenzene or glucose, or the matrix may be of such substances as bentonite, powdered carbon, titania, alumina or glass. Preferred catalyst is one in which Proteus rettgeri cells containing penicillin acylase are immobilized by the process of U.S. Pat. No. 3,957,580. Such particulate catalysts will normally have an activity of from about 200 to 5,000 units (micromoles penicillin G deacylated per hour) per gram of dry catalyst.The particulate catalyst is utilized in the form of a shallow bed through which the process stream is rapidly recirculated. By shallow bed is meant a bed having a depth of up to about 6 cm. The actual depth of the bed is determined by the desired productivity of the conversion unit, the activity of the particulate catalyst and, in the case of immobilized microbial cell catalyst, the concentration of cells in the particulate catalyst. The bed should be deep enough to supply sufficient enzyme activity for the desired productivity of the unit and not so deep as to prevent the desired flow discussed hereinafter. At times it may be advisable to admix the catalyst with a particulate material such as diatomaceous earth, perlite or powdered cellulose added in the amount of up to about 80 volume percent of the bed to give the bed a more porous structure. Beds about 1 to 6 cm deep normally meet the desired productivity and flow requirements. Particularly suitable units for preparing such beds include standard filtration equipment such as a horizontal pressure leaf filter or a plate-and-frame filter press.The conversion is run under controlled temperature as well as pH conditions to maximize productivity while minimizing substrate, product and catalyst degradation. The temperature is limited to between about 15.degree. to 45.degree. C and preferably between about 35.degree. and 40.degree. C. The activity of the catalyst drops off considerably at temperatures much below 15.degree. C while temperatures much above 45.degree. C result in considerable decomposition of the penicillin and 6-APA and appreciable denaturization of the catalyst. As indicated hereinbefore, pH control is critical to high conversion of penicillin to 6-APA, and the pH of the process is therefore limited to from about 6.5 to 9.0. A pH much below 6.5 results in considerably reduced enzyme activity and in enhanced penicillin degradation, while a pH much greater than 9.0 accelerates not only penicillin degradation but also enzyme denaturization. The pH is preferably maintained between about 7.5 and 8.2 when the catalyst is derived from Proteus rettgeri.In practice, the bulk of the process stream is maintained at the desired temperature and pH in a stirred tank or reservoir. A small portion of the stream is continuously passed through the catalyst bed and quickly returned to the reservoir where the acid formed during the passage through the bed is neutralized by a suitable base such as sodium hydroxide to maintain the pH within the desired range. Such a system can be adapted to batch, semi-continuous or continuous operation.The flow rate of the process stream through the catalyst bed is also of critical importance in assuring optimum conversion of penicillins to 6-APA, and should be at least 0.4 bed volume per minute. Flow rates much below this value not only cause a considerable reduction of catalyst utilization resulting from poorer diffusion of the substrate and product within the catalyst bed but also enhance the degradation of substrate, product and catalyst from the increase localized acidity present in the bed.The recycling of the process stream through the catalyst bed is continued until the penicillin in the stream has been substantially (at least 80 percent) converted. The 6-APA in the stream may then be either isolated or reacted to a desired penicillin by conventional means.

    Abstract translation: 在床上，该方法具有利用标准工艺设备的进一步优点。

    ENZYME-IMMOBILIZED POROUS MEMBRANE AND PREPARATION METHOD OF ANTIBIOTICS USING THE SAME
    5.
    发明申请
    ENZYME-IMMOBILIZED POROUS MEMBRANE AND PREPARATION METHOD OF ANTIBIOTICS USING THE SAME 审中-公开

    公开(公告)号：US20200063175A1

    公开(公告)日：2020-02-27

    申请号：US16658705

    申请日：2019-10-21

    Applicant: GWANGJU INSTITUTE OF SCIENCE AND TECHNOLOGY

    Inventor： Ji-woong PARK ,  Sunoh Shin

    IPC: C12P37/04 ,  C12N9/84 ,  C12N11/08

    Abstract: The present disclosure relates to an enzyme-immobilized porous membrane and a preparation method of antibiotics using the same, and more specifically, to an enzyme-immobilized porous membrane prepared by immobilizing a specific enzyme through dead-end filtration, and a preparation method of antibiotics with a high yield using the enzyme-immobilized porous membrane.According to various exemplary embodiments of the present disclosure, the enzyme capable of promoting the synthesis reaction of the antibiotic substance is able to be stably immobilized in the porous membrane by passing the solution of enzyme through the membrane.In addition, it is possible to provide antibiotics with a high yield by preparing the antibiotics by passing the reactant solution through the enzyme-immobilized porous membrane.

    Bioprocesses for preparing 7-ACA and 7-ADAC
    7.
    发明授权
    Bioprocesses for preparing 7-ACA and 7-ADAC 失效
    用于制备7-ACA和7-ADAC的生物工艺

    公开(公告)号：US6071713A

    公开(公告)日：2000-06-06

    申请号：US340781

    申请日：1999-06-28

    Applicant: Michael J. Conder ,  John A. Rambosek ,  Phyllis C. McAda ,  Christopher D. Reeves

    Inventor： Michael J. Conder ,  John A. Rambosek ,  Phyllis C. McAda ,  Christopher D. Reeves

    IPC: C12N1/19 ,  C07D501/20 ,  C12N1/15 ,  C12N9/00 ,  C12N9/02 ,  C12N9/10 ,  C12N15/09 ,  C12N15/52 ,  C12N15/54 ,  C12P20060101 ,  C12P35/00 ,  C12P35/06 ,  C12P37/04 ,  C12R1/82 ,  C12N1/14 ,  C12N1/20 ,  C12P35/02

    CPC classification number: C12N9/0071 ,  C12N9/00 ,  C12N9/1029 ,  C12P35/00 ,  C12P37/04 ,  Y10S435/935

    Abstract: A bioprocess for preparing adipoyl-7-ACA comprising the steps: (a) transforming cells of a strain of Penicillium chrysogenum which produces isopenicillin N with an expression vector containing DNA encoding an enzyme, having expandase activity capable of accepting adipoyl 6-APA as a substrate, an enzyme having hydroxylase activity capable of accepting adipoyl-7-ADCA as a substrate and an enzyme having acetyl transferase activity capable of accepting adipoyl 7-ADAC as a substrate; (b) culturing the transformed cells from step a) in a suitable culture medium containing an adipate feedstock, wherein said cells produce adipoyl 6-APA; and (c) culturing the transformed cells producing adipoyl 6-APA of step b) under conditions suitable for expression of said DNA encoding enzyme, thereby producing the end product adipoyl-7-ACA.

    Abstract translation: 一种用于制备己二酰-7-ACA的生物工艺，包括以下步骤：（a）用含有编码酶的DNA的表达载体转化产生异青霉素N的产青霉菌菌株的细胞，其具有能够接受己二酰基6-APA的扩环酶活性 底物，能够接受己二酰-7-ADCA作为底物的羟化酶活性的酶和能够接受己二酰基7-ADAC作为底物的乙酰转移酶活性的酶; （b）在含有己二酸原料的合适培养基中培养来自步骤a）的转化细胞，其中所述细胞产生己二酰基6-APA; 和（c）在适于表达所述DNA编码酶的条件下培养产生步骤b）的己二酰基6-APA的转化细胞，从而产生最终产物己二酰-7-ACA。

    Enzymatic acylation to afford .beta.-lactam antibiotics
    9.
    发明授权
    Enzymatic acylation to afford .beta.-lactam antibiotics 失效
    酶法酰化得到{62-内酰胺抗生素

    公开(公告)号：US4073687A

    公开(公告)日：1978-02-14

    申请号：US686219

    申请日：1976-05-12

    Applicant: Eiji Kondo ,  Takashi Mitsugi

    Inventor： Eiji Kondo ,  Takashi Mitsugi

    IPC: C07D499/12 ,  C07D499/64 ,  C07D501/06 ,  C07D501/22 ,  C07D501/32 ,  C12P35/04 ,  C12P37/04 ,  C12D1/02

    CPC classification number: C12P35/04 ,  Y10S435/911 ,  Y10S435/925

    Abstract: Penicillin or cephalosporin antibiotics represented by following formula: ##STR1## where ##STR2## is an acyl group derived from an .alpha.-amino acid, N-ammonium salt of .alpha.-amino acid, or N--(C.sub.1 to C.sub.10) acyl-.alpha.-amino acid; COOM is carboxy or carboxylate salt group!Are prepared by treating an amino compound selected from a group consisting of 6-aminopenicillanic acid, 7-aminocephalosporanic acid, 7-aminodeacetoxycephalosporanic acid, and their salts with an ester represented by following formula:RCOOR.sup.1 where ##STR3## is as defined above and R.sup.1 is a (C.sub.1 to C.sub.10) alkyl group! BY ENZYMATIC ACYLATION EFFECTED WITH MYCELIUM OR MYCELIUM PREPARATION FROM A MICROORGANISM BELONGING TO GENUS Aphanocladium or Cephalosporium.

    Abstract translation: 由下列化学式表示的青霉素或头孢菌素抗生素： 其中是衍生自α-氨基酸，α-氨基酸N-铵盐或N-（C1 至C10）酰基-α-氨基酸; COOM是羧基或羧酸盐基团]通过处理由含有6-氨基苯甲酸，7-氨基戊酸，4-氨基乙酰氧基苯甲酸的组合选择的氨基化合物及其与以下公式表示的酯的盐：

    Application of enzyme prodrugs as anti-infective agents
    10.
    发明授权
    Application of enzyme prodrugs as anti-infective agents 有权
    酶前药作为抗感染剂的应用

    公开(公告)号：US6159706A

    公开(公告)日：2000-12-12

    申请号：US215688

    申请日：1998-12-18

    Applicant: H. Michael Shepard

    Inventor： H. Michael Shepard

    IPC: G01N33/50 ,  A61K31/43 ,  A61K31/545 ,  A61K31/546 ,  A61K47/48 ,  A61P31/04 ,  C07D501/20 ,  C12P35/00 ,  C12P37/04 ,  C12Q1/04 ,  C12Q1/18 ,  G01N33/15 ,  A61K38/00 ,  C12Q1/26 ,  C07D5/00

    CPC classification number: A61K31/545 ,  A61K47/65 ,  C12Q1/18

    Abstract: The present invention provides a method for targeting toxic antimetabolites to gram negative infections. It provides a means of taking advantage of a key disease resistance mechanism to activate these drugs locally, and to overcome the resistance phenotype of the microbes. The invention further provides a method for selecting for antibiotic sensitivity, since a likely mechanism by which organisms are likely to gain resistance to the prodrugs is via loss of enzyme activity, which will make the bacteria sensitive to antibiotics once again.

    Abstract translation: 本发明提供了一种用于将有毒抗代谢物靶向革兰氏阴性感染的方法。 它提供了一种利用关键疾病抵抗机制来局部激活这些药物的手段，并克服了微生物的抗性表型。 本发明还提供了选择抗生素敏感性的方法，因为生物体可能获得对前体药物抗性的可能机制是通过酶活性的丧失，这将使细菌再次对抗生素敏感。

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