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OwnerMarcus Horwitz, Gunter Harth +2inventors
InventorsMarcus Horwitz, Gunter Harth, Paul Zamecnik, David Tabatadze
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Methods of inhibiting the proliferation of Mycobacterium tuberculosis comprising contacting Mycobacterium tuberculosis with an effective amount of a polynucleotide complementary to an mRNA transcript expressed by Mycobacterium tuberculosis are provided. Typical methods of the invention utilize phosphorothioate modified antisense polynucleotides (PS-ODNs) against the mRNA of M. tuberculosis genes such as glutamine synthetase, aroA, ask, groES, and the genes of the Antigen 85 complex. Optionally, the methods employ multiple antisense polynucleotides targeting different Mycobacterium tuberculosis transcripts. In preferred embodiments of the invention, the antisense polynucleotides are complementary to the 5′ regions of the Mycobacterium tuberculosis transcripts.
A method of inhibiting the proliferation of a Mycobacterium tuberculosis bacteria comprising contacting the bacteria with at least two antisense polynucleotides that recognize distinct Mycobacterium tuberculosis mRNA transcripts selected from the group consisting of the Mycobacterium tuberculosis mRNA transcript that encodes the 30 kd major secretory protein (Antigen 85B), the Mycobacterium tuberculosis mRNA transcript that encodes the 32A kd major secretory protein (Antigen 85A), and the Mycobacterium tuberculosis mRNA transcript that encodes the 32B kd major secretory protein (Antigen 85C), wherein the 30 kd major secretory protein (Antigen 85B) mRNA transcript hybridizes to a polynucleotide having the sequence shown in SEQ ID NO:
A method of inhibiting the proliferation of a Mycobacterium tuberculosis bacteria comprising contacting the bacteria with an effective amount of an antisense polynucleotide that is complementary to a Mycobacterium tuberculosis mRNA transcript selected from the group consisting of the Mycobacterium tuberculosis mRNA transcript that encodes the 30 kd major secretory protein (Antigen 85B), the Mycobacterium tuberculosis mRNA transcript that encodes the 32A kd major secretory protein (Antigen 85A), and the Mycobacterium tuberculosis mRNA transcript that encodes the 32B kd major secretory protein (Antigen 85C), wherein the antisense polynucleotide is complementary to a region that is within 100 nucleotides of the of the 5′ nucleotide of the mRNA transcript, and wherein the antisense polynucleotide hybridizes to the mRNA transcript and inhibits the expression of the protein encoded by the transcript.
A method of inhibiting the proliferation of a Mycobacterium tuberculosis bacteria comprising contacting the bacteria with at least two antisense polynucleotides that are complementary to at least two different Mycobacterium tuberculosis mRNA transcripts, wherein the Mycobacterium tuberculosis mRNA transcripts hybridize under stringent conditions to polynucleotides having the sequence 5′-AAT CTT TCG GCT CAC GTC TGT CAT-3′ (SEQ ID NO:
A method of inhibiting Mycobacterium tuberculosis glutamine synthetase protein expression comprising contacting a Mycobacterium tuberculosis bacterium with an effective amount of an antisense compound comprising an antisense polynucleotide that hybridizes to a Mycobacterium tuberculosis glutamine synthetase polynucleotide, wherein the antisense polynucleotide hybridizes to a region of the Mycobacterium tuberculosis glutamine synthetase polynucleotide encoding the glutamine synthetase protein, thereby inhibiting Mycobacterium tuberculosis glutamine synthetase protein expression.
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