Antisense antibacterial compounds and methods

An antisense morpholino oligomer of formula (VII) selected from:

• or a pharmaceutically acceptable salt of any of the foregoing,
• wherein Ra is H or acetyl,
• each Nu is a nucleobase which taken together forms a targeting sequence, and the targeting sequence is selected from:
• f) SEQ ID NO:
• 11 (TCA AGT TTT CC);
• g) SEQ ID NO:
• 12 (TCC TTT TAT TC);
• h) SEQ ID NO:
• 13 (CCA TCA AGT TT);
• i) SEQ ID NO:
• 14 (GGC AAT TCC AT);
• j) SEQ ID NO:
• 15 (ATA CTG TCC AA);
• wherein X is 9, and thymine bases (T) may be uracil bases(U).

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an antisense morpholino oligomer of formula (I):

• or a pharmaceutically acceptable salt thereof,
• where each Nu is a nucleobase which taken together forms a targeting sequence;
• X is an integer from 9 to 38;
• T is selected from OH and a moiety of the formula:
• where each R4 is independently C1-C6 alkyl, and R5 is selected from an electron pair and H, and R6 is selected from OH, —N(R7)CH2C(O)NH2, and a moiety of the formula:
• where:
• R7 is selected from H and C1-C6 alkyl, and
• R8 is selected from G, —C(O)—R9OH, acyl, trityl, and 4-methoxytrityl, where:
• R9 is of the formula —(O-alkyl)y- wherein y is an integer from 3 to 10 and each of the y alkyl groups is independently selected from C2-C6 alkyl;
• each instance of R1 is —N(R10)2R11 wherein each R10 is independently C1-C6 alkyl, and R11 is
• selected from an electron pair and H;
• R2 is selected from H, G, acyl, trityl, 4-methoxytrityl, benzoyl, stearoyl, and a moiety of the formula:
• where L is selected from —C(O)(CH2)6C(O)— and —C(O)(CH2)2S2(CH2)2C(O)—, and each R12 is of the formula —(CH2)2OC(O)N(R14)2 wherein each R14 is of the formula —(CH2)6NHC(═NH)NH2;
• and
• R3 is selected from an electron pair, H, and C1-C6 alkyl,
• wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from
• —C(O)(CH2)5NH—CPP, —C(O)(CH2)2NH—CPP, —C(O)(CH2)2NHC(O)(CH2)5NH—CPP,
• and —C(O)CH2NH—CPP, or G is of the formula:
• wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that only one instance of G is present,
• wherein the targeting sequence specifically hybridizes to a bacterial mRNA target sequence that encodes a virulence factor, and
• wherein the targeting sequence is selected from:
• k) SEQ ID NO:
• 11 (TCA AGT TTT CC);
• l) SEQ ID NO:
• 12 (TCC TTT TAT TC);
• m) SEQ ID NO:
• 13 (CCA TCA AGT TT);
• n) SEQ ID NO:
• 14 (GGC AAT TCC AT);
• o) SEQ ID NO:
• 15 (ATA CTG TCC AA);
• wherein X is 9, and thymine bases (T) may be uracil bases(U).