Molecular tools for rapid identification and novel effective therapy against MDRTB/XDRTB infections

Abstract

Tuberculosis (TB) is mainly an intracellular infection of the lung alveolar macrophages, and any anti-TB agent must therefore be active at the macrophage. Among the available therapies, isoniazid and rifampicin are the most effective drugs against susceptible Mycobacterium tuberculosis, but they are ineffective against multidrug-resistant TB (MDRTB) strains. Rates of MDRTB in Portugal are the highest in Western Europe, demanding effective measures for their control. Our application of molecular techniques for the early identification of MDRTB assisted in the reduction of these rates. Further examination revealed that a large number of MDRTB cases were extensively-drug resistant (XDRTB), providing evidence for the urgent need of new and effective anti-MDRTB/XDRTB therapeutic strategies. This review describes in detail: the characteristics of the main M. tuberculosis strains circulating in Portugal; the creation of a Task Force for TB control, based on molecular tools that allow 1-day identification of an MDRTB patient; the usefulness of evaluating the ex vivo activity of anti-tubercular agents against the M. tuberculosis isolated from the patient’s sputum; and the mode of action by which phenothiazines have been shown to promote the killing of intracellular MDRTB/XDRTB by nonkilling macrophages.

Keywords::

• macrophages
• MDRTB
• multidrug resistance
• phenothiazines
• tuberculosis
• XDRTB

Acknowledgements

The authors wish to thank João V Costa for the support he provided for the creation of the new Mycobacteriology Laboratory. The authors are also grateful for the participation of the physicians and laboratory personnel from hospitals involved in the TB Task Force Program for Greater Lisbon, namely: Hospital Egas Moniz (Lisboa), Hospital Fernando da Fonseca (Amadora-Sintra), Hospital Garcia da Orta (Almada), Hospital Condes de Castro Guimarães (Cascais), Hospital de Nossa Senhora do Rosário (Barreiro), Hospital de São Bernardo (Setúbal), Hospital Pulido Valente (Lisboa), Hospital Santa Maria (Lisboa), Hospital de Santa Cruz (Lisboa), Hospital São Francisco Xavier (Lisboa), Hospital dos Capuchos (Lisboa) and Hospital Prisional de Caxias (Oeiras).

The authors are also grateful for the support in establishing global clinical trials with thioridazine for the therapy of extensively-drug resistant TB from the following colleagues: José Ainsa (Zaragoza, Spain), Francisco Antunes (Lisbon, Portugal), German Bou (Coruña, Spain), Franz Bucar (Graz, Austria), Emilia Crisan, (Bucharest, Roumania), Sujata Dastidar (Calcuta, India), Séamus Fanning (Dublin, Ireland), Paulo Ferrinho (Lisbon, Portugal), Julia Gonzales Martín (Barcelona, Spain), Gareth Griffith (Oslo, Norway), Eamonn Gormley (Dublin, Ireland), Winfried V Kern (Freiburg, Germany), Hans J Kolmos (Odense, Denmark), Jette E Kristiansen (Sonderborg, Denmark), Joseph Molnar (Szeged, Hungary), Jean-Marie Pages (Marseille, France), Mihail Pascu (Bucharest, Romania), Spyros Pournaras (Larissa, Greece), Max Salfinger (FL, USA), Mohsin Sidat (Maputo, Mozambique), George Tegos (MA, USA), Jakko van Ingen (Bilthoven, The Netherlands), Andras Varga (Berlin, Germany), Jordi Vila (Barcelona, Spain), Rolf Walter (Hamburg, Germany) and Kanglin Wan (Beijing, China).

Financial & competing interests disclosure

This work was supported by grants SDH.IC.I.01.17-TB Task Force for Greater Lisbon (2001), TB-Fast-Track Program (2004) and XDRTB Early Detection in Greater Lisbon (2009) from the Calouste Gulbenkian Foundation. This work was also supported by grants EU-FSE/FEDER-POCI/SAU-MMO/59370/2004 and EU-FSE/FEDER-PTDC/BIA-MIC/71280/2006 provided by the Fundação para a Ciência e a Tecnologia (FCT) of Portugal. Marta Martins and Liliana Rodrigues were supported by grants SFRH/BD/14319/2003 and SFRH/BD/24931/2005 (FCT, Portugal), respectively. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.