One of the reasons tuberculosis (TB) continues to be a substantial public health problem is because the bacteria that cause TB, Mycobacterium tuberculosis, develop drug tolerance quickly. This requires patients to follow a 6-month-long drug regimen to ensure bacterial eradication, to which many patients fail to adhere. In order to identify new drug targets that may lead to shorter therapeutic regimens, Adams et al. dissected the development of drug tolerance in a zebrafish model of TB. Zebrafish infection with Mycobacterium marinum followed a similar disease course as human infection, which included the rapid development of drug tolerance. Multidrug-tolerant bacteria were present in macrophages just days after infection and were expanded and disseminated by granulomas. Bacteria acquired tolerance by replicating in macrophages, in both fish and mammalian cells. Upon infection, macrophages increased expression of bacterial efflux pumps, which can pump drugs out. Use of pump inhibitors demonstrated that these complexes mediated drug tolerance. Together, these studies suggest that adding efflux pump inhibitors to the standard TB therapies may be an effective way to reduce the course of treatment.

source: Cell