Avaliação pré-clínica dos compostos IQG-607 e IQG-639 em um modelo de tuberculose em camundongos

Abstract

Tuberculosis continues to be one of the deadliest diseases in the world. The emergence of drug-resistant strains of Mycobacterium tuberculosis, the unbearable side effects of the available drugs and the frequent patient non-compliance in completing the therapy have increased the need for development of new effective agents. We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639 against the M. tuberculosis enoyl-ACP reductase enzyme. Importantly, IQG-607 and IQG-639 were active against cultures of M. tuberculosis H37Rv and two isoniazid-resistant clinical isolates in vitro. In the present study, the activity of these compounds was evaluated by using an in vivo murine model of tuberculosis. Swiss mice were infected with M. tuberculosis H37Rv strain, and IQG-607 and IQG-639 (250 mg/kg) were administered during 28 or 56 days. As well, a dose-response study was performed with IQG-607 (at 5, 10, 25, 50, 100, 200 and 250 mg/kg). The activity of test compounds was compared with that of the positive control drug isoniazid at 25 mg/kg. After 28 or 56 days of treatment, either IQG-607 or isoniazid significantly reduced M. tuberculosis-induced splenomegaly, and also significantly diminished the colony-forming units in both spleens and lungs. IQG-607 or isoniazid ameliorated the lung macroscopic aspect, reducing the lung lesions to a similar extent. However, IQG-639 was not capable of significantly modifying any evaluated parameter. IQG-607 did not display a classical dose-dependent profile in our murine model of tuberculosis, and 10 mg/kg was the lowest dose able to show significant activity, which was similar to the inhibition observed for higher doses. In addition, experiments using early and late controls of infection revealed a bactericidal activity for IQG-607 in our model. The promising activity of IQG-607 in M. tuberculosis-infected mice suggests that this compound might represent a good candidate for clinical development as a new antimycobacterial agent.