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)-3,7,11,1 7-tetraaza-bicyclo[11.3.1]heptadeca- 1(17),13,15-triene, abbreviated as ac( 3)py14, was investigated for its activity against Mycobacterium tuberculosi s and for induction of protective cellular immune responses. Perspective re sults show that ac(3)py14 and its Fe3+ 1:1 complex, [Fe(ac(3)py14)], inhibi ted radiometric growth of several strains of M. tuberculosis. Inhibition wi th 25 mug/mL varied from 99% for H37Rv to 80% and above for multiple drug-r esistant clinical isolates. The capacity of ac(3)py14 to elicit a beneficia l immune response without cellular apoptosis was assessed and compared to t he effects of virulent M. tuberculosis. The present study produces evidence that after stimulation with ac(3)py 14 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 sufficie nt to result in toxic effects toward alpha beta and gamma delta T cells and CD14(+) macrophages. This preliminary study is the first report of a compo und that simultaneously exerts an inhibitory effect against M. tuberculosis and induces factors associated with protective immune responses. (C) 2001 Editions scientifiques et medicales Elsevier SAS.