Antisense antibacterial method and compound
View Patent ↗A method and antisense compound for inhibiting the growth of pathogenic bacterial cells are disclosed. The compound contains no more than 12 nucleotide bases and has a targeting nucleic acid sequence of no fewer than 10 bases in length that is complementary to a target sequence containing or within 10 bases, in a downstream direction, of the translational start codon of a bacterial mRNA that encodes a bacterial protein essential for bacterial replication. The compound binds to a target mRNA with a T m of between 50° to 60° C. The relatively short antisense compounds are substantially more active than conventional antisense compounds having a targeting base sequence of 15 or more bases.
1. A method of inhibiting the growth of pathogenic bacterial cells, comprising exposing the bacterial cells to a growth-inhibiting amount of a substantially uncharged antisense morpholino oligomer having a sequence consisting of SEQ ID NO: 109,
wherein said morpholino oligomer is composed of morpholino subunits and phosphorodiamidate intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit.
2. The method of claim 1 , wherein the morpholino subunits in the morpholino oligomer to which the cells are exposed are joined by phosphorodiamidate linkages, in accordance with the structure:
where Y 1 =O, Z=O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is alkyl, alkoxy, thioalkoxy, amino, or —NR 2 , where each R is independently hydrogen or methyl.
3. The method of claim 1 , for use in inhibiting a bacterial infection in a mammalian subject, wherein said exposing includes administering said morpholino oligomer in a therapeutically effective amount.
4. The method of claim 3 , which further includes treating the subject by administration of a non-antisense compound having antibacterial activity.
5. The method of claim 1 , wherein the morpholino subunits in the oligonucleotide compound are joined by phosphorodiamidate linkages, in accordance with the structure:
where
Y 1 =O,
Z=O,
Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and
X is alkyl, alkoxy, thioalkoxy, amino, alkyl amino, dialkylamino, or 1-piperazinyl, wherein X is 1-piperazinyl in at least one linkage and up to about 1 of every 5 linkages.