Multidrug- and
extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of
phenothiazines as antimicrobial drugs. Within this pharmacological class we selected
thioridazine, which is most efficacious and least toxic, when used as an
antipsychotic drug. We tested
thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and
multidrug-resistant tuberculosis by a two months daily
oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible
tuberculosis.
Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (-4.4 log CFU, p<0.05) and
multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after
infection, compared to controls. Moreover, when
thioridazine was added to a regimen containing
rifampicin,
isoniazid and
pyrazinamide for susceptible
tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01).
Thioridazine may represent an effective compound for treatment of susceptible and
multidrug-resistant tuberculosis. The
phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs.