Antisense antibacterial cell division composition and method
View Patent ↗Antisense oligomers directed to bacterial cell division and cell cycle-encoding nucleic acids are capable of selectively modulating the biological activity thereof, and are useful in treatment and prevention of bacterial infection. The antisense oligomers are substantially uncharged, and contain from 8 to 40 nucleotide subunits, including a targeting nucleic acid sequence at least 10 nucleotides in length which is effective to hybridize to (i) a bacterial tRNA or (ii) a target sequence, containing a translational start codon, within a bacterial nucleic acid which encodes a protein associated with cell division or the cell cycle. Such proteins include zipA, sulA, secA, dicA, dicB, dicC, dicF, ftsA, ftsI, ftsN, ftsK, ftsL, ftsQ, ftsW, ftsZ, murC, murD, murE, murF, murG, minC, minD, minE, mraY, mraW, mraZ, seqA, ddlB, carbamate kinase, D-ala D-ala ligase, topoisomerase, alkyl hydroperoxide reductase, thioredoxin reductase, dihydrofolate reductase, and cell wall enzyme.
1. A substantially uncharged antisense oligomer containing 10 to 40 morpholino subunits, each of said subunits supporting a base-pairing moiety effective to bind by Watson-Crick base pairing to a respective nucleotide base,
wherein said base-pairing moieties include a targeting nucleic acid sequence having the sequence presented as SEQ ID NO: 47,
and wherein adjacent subunits are joined by uncharged linkages selected from the group consisting of uncharged phosphoramidate and phosphorodiamidate, or by charged linkages selected from the group consisting of charged phosphoramidate and phosphorodiamidate, the ratio of uncharged linkages to charged linkages in the oligomer being at least 4:1.
2. The oligomer of claim 1 , wherein each said uncharged linkage is a phosphorodiamidate linkage as represented by —P(═O)(NR 2 )—O—, where R is hydrogen or methyl.
3. The oligomer of claim 2 , wherein each said linkage in said oligomer is an uncharged phosphorodiamidate linkage as represented by —P(═O)(NR 2 )—O—, where R is hydrogen or methyl.
4. The oligomer of claim 1 , wherein the length of said oligomer is less than 30 subunits.
5. The oligomer of claim 1 , wherein the length of said oligomer is less than 25 subunits.
6. The oligomer of claim 1 , wherein the length of said oligomer is 20 subunits.