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Thioridazine and other helper compounds as enhancers of the killing activity of macrophages infected with Mycobacterium tuberculosis: correlation with the curing of infected mice

Abstract number: O340

Martins M., Viveiros M., Amaral L.

Objectives: The emergence of Multi-Drug Resistant and Extensively-Drug Resistant Mycobacterium tuberculosis (MDRTB/XDRTB) represents a major threat to public health worldwide, as many of these resistant strains are untreatable with available drugs. In order to control these infections, there is the need for new and non-toxic antimicrobial compounds. Phenothiazines have been shown to have direct and indirect activities against a large gamut of bacteria and may be considered for the therapy of these infections. We have demonstrated with previous studies that Thioridazine (TZ) enhances the killing of MDRTB phagocytosed by human monocyte-derived macrophages. However, the mechanism by which this agent enhances the killing of intracellular bacteria is not fully understood. The killing activity of some phagocytic cells, such as the neutrophils have been demonstrated to be correlated with the K+ availability which is dependent upon transport processes affected by agents that inhibit Ca2+-activated K+ pumps. In order to clarify the mechanism by which TZ enhances the killing activity of infected macrophages, we have studied the activity of TZ, twenty-two TZ derivatives, ouabain, reserpine and verapamil (other known inhibitors of K+ and Ca2+ transport) against intracellular bacteria.

Methods: Ex vivo studies were conducted using human monocyte-derived macrophages infected with MDRTB and subsequently treated with TZ, its derivatives and other inhibitors of K+ and Ca2+ transport. Animal studies were conducted using BALB/c mice infected with M. tuberculosis and daily treated with different doses of TZ. The bacterial load in the lungs was monthly assessed by CFU counting.

Results: Each of these compounds enhanced the killing of intracellular MDRTB ex vivo and TZ showed a significant effect in the mouse curing of the M. tuberculosis infection.

Conclusion: Because each of these compounds also inhibit Ca2+ and K+ transport processes, enhanced killing is postulated to be due to the inhibition of Ca2+ and K+ transport, processes which when inhibited promote the activation of hydrolases and subsequent killing of intracellular bacteria. A model that provides the sequence of events that lead to killing of intracellular bacteria by non-killing human macrophages will be presented in detail and related to the curing of BALB/c mice infected with M. tuberculosis by administration of TZ at dose and interval equivalent to that employed for the therapy of psychosis.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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