Editors' ChoiceTuberculosis

Fishing for Answers

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Science Translational Medicine  20 Apr 2011:
Vol. 3, Issue 79, pp. 79ec55
DOI: 10.1126/scitranslmed.3002507

Despite the availability of triple drug therapy (isoniazid, rifampicin, and pyrazinamide), the incidence of tuberculosis (TB) and the emergence of drug-resistant forms of the disease remain a major global health concern. Treatment of TB is particularly difficult because the antibiotic combination therapy must be administered for 6 months to prevent the TB pathogen, Mycobacterium tuberculosis, from becoming resistant to the drugs. In a new study in Cell, Ramakrishnan and colleagues go fishing for some answers to the tough question of how drug tolerance emerges in mycobacteria.

They chose to study TB not in the usual mouse model but in zebrafish larvae infected with the mycobacterium M. marinum, which they were able to quantify and track using green fluorescent protein. This fish model reproduces many of the features of M. tuberculosis infection in humans, including formation of granulomas, complex tissue structures containing mycobacteria, and immune cells such as macrophages.

The researchers netted several unexpected findings. First, contrary to the prevailing view that drug tolerance in TB is due to nonreplicating, metabolically quiescent mycobacteria, the authors report that drug-tolerant M. marinum inside fish macrophages actively replicated and were metabolically active. Despite rapid treatment of the infected zebrafish larvae with rifampicin and isoniazid, the researchers discovered that the drug-tolerant mycobacteria persisted inside the macrophages and were disseminated throughout the organism by granulomas.

To discover the mechanism of mycobacterial drug tolerance, the investigators then turned to cultured macrophages infected with M. marinum. They show that infected macrophages induce the mycobacteria to express efflux pump proteins that pump out the antimicrobial drugs from the bacteria before they can exert a microbicidal effect. The investigators were able to decrease drug tolerance in M. marinum using the efflux pump inhibitors verapamil or reserpine. These exciting findings from a fruitful fishing expedition suggest that a clinical trial in which verapamil or reserpine (which have already received FDA approval) are added to the current triple drug therapy for TB is warranted. Addition of these efflux pump inhibitors may prevent the emergence of drug-resistant M. tuberculosis, thus leading to a reduction in the length of time that patients must stay on the drugs.

K. N. Adams et al., Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145, 39–53 (2011). [PubMed]

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