Use of type-B lantibiotic-based compounds having antimicrobial activity

A method for the treatment of a microbial infection of the lower intestine or colon in a subject in need there of, the method comprising administering to the subject a type-B lantibiotic of formula (Ia):

• wherein the type-B lantibiotic has antimicrobial activity, and
• wherein:
• X1 represents Leu;
• Val;
• or Ile;
• X2 represents Leu;
• Val;
• or Ile;
• X is —OH or —NR1AR2A, wherein R1A represents hydrogen, or an alkyl or heteroalkyl group, substituted by at least one hydroxyl substituent, and R2A represents hydrogen, or an alkyl or heteroalkyl group, substituted by at least one hydroxyl substituent, or R1A and R2A 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, or R1A and R2A independently represent:
• (1) hydrogen;
• (2) a group of formula —(CH2)n—NR11R12, in which n represents an integer from 2 to 12 and R11 and R12 independently represent hydrogen or (C1-C4) alkyl or R11 and R12 taken together represent a group —(CH2)3—, —(CH2)4—, —(CH2)2—O—(CH2)2, —(CH2)2—S—(CH2)2—or —(CH2)5—;
• or R1A and R2A taken together with the adjacent nitrogen atom represent a piperazine which may be substituted in position 4 with a substituent selected from:
• (a) (C1-C4)alkyl;
• (b) (C5-C2)-cycloalkyl,
• (c) pyridyl,
• (d) —(CH2)p—NR13R14 in which p represents an integer from 1 to 8 and R13 and R14 independently represent hydrogen or (C1-C4) alkyl;
• (e) piperidinyl;
• (f) substituted piperidinyl, wherein the substituted piperidinyl bears a N-substituent which is (C1-C4)alkyl;
• (g) benzyl;
• and
• (h) substituted benzyl, wherein a phenyl therein bears 1 or 2 substituents selected from chloro, bromo, nitro, (C1-C4)alkyl and (C1-C4)alkoxy;
• Z is an amino acid residue,
• —NR3R4, —NR5COR6, —NR5C(O)OR6;
• —NR5SOR6, —NR5SO2R6;
• —NR5C(S)NR6R7, —NR5C(NR8)NR6R7, or —N=R9, wherein each of these groups represents modifications of the N-terminus of the amino acid at position 1, and 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)—;
• or a variant, derivative, pharmaceutically acceptable salt thereof,
• wherein a variant is a compound where 1, 2, 3 or 4 amino acids at positions 2, 3, 4, 5, 8, 10, 11, 13 or 18 are substituted by another amino acid, and the another amino acid is a naturally occurring amino acid or its D-isoform,
• and a derivative is a compound where the carboxy function of a side chain of an internal residue, is modified from —COOH to a group —COOR9 in which R9 represents (C1-C4)alkyl or (C1-C4)alkoxy(C2-C4)alkyl.