Activity against Mycobacterium tuberculosis with concomitant induction of cellular immune responses by a tetraaza-macrocycle with acetate pendant arms.
The novel tetraaza-macrocyclic compound 3,7,11-tris(carboxymethyl)-3,7,11,17-tetraaza-bicyclo[11.3.1]heptadeca-1(17),13,15-triene, abbreviated as ac3py14, was investigated for its activity against Mycobacterium tuberculosis and for induction of protective cellular immune responses. Perspective results show that ac3py14 and its Fe3+ 1:1 complex, [Fe(ac3py14)], inhibited radiometric growth of several strains of M. tuberculosis. Inhibition with 25 microg/mL varied from 99% for H37Rv to 80% and above for multiple drug-resistant clinical isolates. The capacity of ac3py14 to elicit a beneficial immune response without cellular apoptosis was assessed and compared to the effects of virulent M. tuberculosis. The present study produces evidence that after stimulation with ac3py14 there was significant production of interferon gamma (IFN-gamma), whereas the production of interleukin-5 (IL-5) remained low, and there was development of a memory population (CD45RO). The level of binding of Annexin V, a marker of apoptosis, was not sufficient to result in toxic effects toward alphabeta and gammadelta T cells and CD14+ macrophages. This preliminary study is the first report of a compound that simultaneously exerts an inhibitory effect against M. tuberculosis and induces factors associated with protective immune responses.
David
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Mycobacteriology Unit, Instituto de Higiéne e Medicina Tropical/Universidade Nova de Lisboa, Lisbon, Portugal. suzanadavid@IHMT.UNL.PT
Ordway
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Arroz
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Costa
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Delgado
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D000328:Adult; D017304:Annexin A5 / Q000032:analysis; D000995:Antitubercular Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015169:Colony Count, Microbial; D004352:Drug Resistance, Microbial; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D015848:Interleukin-5 / Q000032:analysis / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology
C445963:3,7,11-tris(carboxymethyl)-3,7,11,17-tetraaza-bicyclo(11.3.1)heptadeca-1(17),13,15-triene; D017304:Annexin A5; D000995:Antitubercular Agents; D006574:Heterocyclic Compounds, 2-Ring; D015848:Interleukin-5; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens