The inventions provides a method of treating a human subject for C. difficile infection comprising administering orally a therapeutically effective dose of an antibiotic (for example 50 mg to 750 mg) which is selective for C. difficile over Gram-negative bacteria which are 5 components of natural healthy gut flora, wherein the average systemic plasma level of the antibiotic and any metabolites thereof does not exceed 5 ng/mL, for example is 4, 3, or 2 ng/mL or less.
Provided are compounds, the use of the said compounds in treatment, for example treatment of microbial infections, particularly by Gram negative bacteria. The compounds are polymyxin-based and are represented by the formula (I): and pharmaceutically acceptable salts thereof, where X is -NHC(O)-, -C(O)-, -OC(O)-, -CH2- or -SO2-; R5 represents C10-12 a!kyl(C4-6 heterocyclyl), or C2-12, ·> alkyl or CO-12 alkyl(C3-8 cycloalkyl), and the alkyl or cycloalkyl bears one, two or three hydroxyl groups, or a -NF6R7 group, or one -NR6R7 group and one or two hydroxy! groups; and R1 to R4 and R6 to R8 are as defined in the description.
Described is a compound of formula (I): wherein X represents a bond or an amino acid residue; R3 represents H or C1-6 alkyl; R4 represents -RA-L-Ar1, or R3 together with R4 and the nitrogen to which they are attached form a 5 or 6 membered heterocyclic group optionally including a further heteroatom selected from N, O or S, wherein said heterocyclic group is substituted by YAr1, where Z, R1, R2, R5, RA, L, Ar1 and Y are further defined.
Described is a compound of formula (I): where R4 represents -RA-L-Ar1, formula (II): or R3 together with R4 and the nitrogen to which they are attached form a 5 or 6 membered heterocyclic group optionally including a further heteroatom selected from N, O or S, wherein said heterocyclic group is substituted by one or two specified groups, and Z, R1, R2, R5, RA, L and Ar1 are further defined.
Described is a A liquid colloidal pharmaceutical formulation of a type B lantibiotic for infusion or direct injection comprising a type B lantibiotic or a salt thereof, an isotonic aqueous solution comprising a sugar alcohol such as glycerol and/or a saccharide and optionally a buffer, wherein said final formulation for infusion or direct injection is clear of visual particulates.
Described is a compound of formula (I): wherein X represents a bond or an amino acid residue; R3 represents H or C1-6 alkyl; R4 represents -RA-L-Ar1, or R3 together with R4 and the nitrogen to which they are attached form a 5 or 6 membered heterocyclic group optionally including a further heteroatom selected from N, O or S, wherein said heterocyclic group is substituted by a specified group, and where Z, R1, R2, R5, RA, L and Ar1 are further defined.
Described is a pharmaceutical formulation of a capsule for oral delivery of a type B lantibiotic to the stomach comprising a hard gelatine, HPMC or starch capsule, and a type B lantibiotic of formula (I): wherein X is -NH(CH2)qNH2 and q is an integer 2 to 12.
Described are lantibiotic-based compounds, pharmaceutical compositions comprising the same and use of the compounds and said compositions, for the treatment of microbial infection, for example Clostridium difficile or Micrococcus luteus infection. The lantibiotic-based compounds have antimicrobial activity and in comparison to one or more of actagardine, actagardine B, deoxyactagardine B and deoxyactagardine have retained activity or improved activity.
Described are certain salts of certain lantibiotic compounds, pharmaceutical compositions comprising the same and use of the salts and compositions for the treatment of microbial infection, particularly Methicillin-resistant Staphylococcus aureus (MRSA) infection. The salts have an aqueous solubility of 2.5 mg/mL or more.
The present disclosure relates to compounds of formula (II): pharmaceutical compositions comprising same and use of the compounds and compositions for the treatment of microbial infection, particularly Methicillin-resistant Staphylococcus aureus (MRSA) infection.
The present invention pertains generally to certain compounds of the deoxyactagardine A and B type. Such compounds are suitable for use in the treatment of microbial infections, for example Clostridium infection, such as C. perfringens, C. difficile, C.tetani, and/or C. botulinum, in particular C. difficile, especially infection of the colon and/or lower intestines and diarrhoea associated with the microbial infection.
The present invention pertains generally to the use of certain compounds derived from actagardine for the treatment of C. difficile infection and/or bacterial overgrowth syndrome, for example in the small intestines and/or colon.
Characterization of the biosynthetic gene cluster for the lantibiotic actagardine, identification of a novel variant of actagardine and its biosynthetic cluster, and methods of production and use of actagardine are described.
The present invention provides methods for the treatment or prophylaxis of a microbial infection of the lower intestine or colon in a subject, the method comprising administering to the subject a type-B lantibiotic. In particular, the invention provides methods for the treatment or prophylaxis of a Clostridium difficile infection. The type-B lantibiotics may include compounds selected from the group consisting of mersacidin, actagardine, plantaricin, planosporicin, ruminococcin, antibiotic 10789, michiganin and haloduracin, and derivatives and variants thereof.
The present invention provides actagardine, actagradine B and deoxy actagardine B derivatives of formula (I), wherein: X1 denotes that the residue is Leu; Val; or Ile; X2 denotes that the residue is Leu; Val; or Ile; R1 represents an alkyl or heteroalkyl group, substituted by at least one hydroxyl substituent, and R2 represents hydrogen, or an alkyl or heteroalkyl group, optionally substituted by at least one hydroxyl substituent, or R1 and R2 taken together with the nitrogen atom represent a heterocyclic group having at least one hydroxyl substituent, wherein the heterocyclic group optionally further contains one or more heteroatoms; Z is an amino acid residue, -NR3R4, -NR5COR6, -NR5C(O)OR6; -NR5SOR6, NR5SO2 R6; -NR5C(S)NR6R7, -NR5C(NR8)NR6R7, or -N=R9, where R3, R4, R5, R6, R7, R8 and R9 are independently hydrogen, or a group, optionally substituted, selected from alkyl, heteroalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, with the proviso that R9 is not hydrogen; and Y is -S- or -S(O)-. The compounds find use in the treatment of microbial infections.
The invention relates to a synthesis method. The method relates to the synthesis of the compound of the formula (I) according to the following diagram A, in which R1, R2, R3 are identical or different and represent an alkyl group, characterised by an enzymatic hydrolysis reaction that comprises contacting the compound of the formula (II) with an enzyme that carries out an chemo-selective hydrolysis of only one of the two ester functions of the compound of the formula (II) in order to obtain the compound of the formula (I). The invention can be used for the industrial preparation of an intermediate product of the formula (I) that can be used for preparing a pharmaceutically active ingredient, i.e. the Repaglinide.
The invention relates to a method for the synthesis of an ester compound of the trans-4-amino-cyclohexane carboxylic acid of formula (I). Said method is characterised in that the ester (I) is obtained, in the form of a salt or otherwise, from a compound of formula (II) by means of a Hoffmann rearrangement reaction and optionally transesterification according to diagram A wherein R represents an alkyl, aryl or alkylaryl grouping. The invention provides a very high yield of said ester in an essentially trans form using a method involving few steps.
C07C 227/04 - Formation of amino groups in compounds containing carboxyl groups
C07C 229/48 - Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
18.
LANTIBIOTIC BIOSYNTHETIC GENE CLUSTERS FROM A. GARBADINENSIS AND A. LIGURIAE
This invention relates to characterisation of the biosynthetic gene cluster for the lantibiotic actagardine, identification of a novel variant of actagardine and its biosynthetic cluster, and methods of production and use of actagardine, a novel actagardine variant, herein referred to as actagardine B, and variants of both of these produced according to this invention, utilizing genes from the characterised biosynthetic gene clusters.
patents
