Abstract
Tuberculosis (TB) is the world’s deadliest curable disease, responsible for an estimated 1.5 million deaths annually. A considerable challenge in controlling this disease is the prolonged multidrug chemotherapy (6 to 9 months) required to overcome drug-tolerant mycobacteria that persist in human tissues, although the same drugs can sterilize genetically identical mycobacteria growing in axenic culture within days. An essential component of TB infection involves intracellular Mycobacterium tuberculosis bacteria that multiply within macrophages and are significantly more tolerant to antibiotics compared to extracellular mycobacteria. To investigate this aspect of human TB, we created a physical cell culture system that mimics confinement of replicating mycobacteria, such as in a macrophage during infection. Using this system, we uncovered an epigenetic drug-tolerance phenotype that appears when mycobacteria are cultured in space-confined bioreactors and disappears in larger volume growth contexts. Efflux mechanisms that are induced in space-confined growth environments contribute to this drug-tolerance phenotype. Therefore, macrophage-induced drug tolerance by mycobacteria may be an effect of confined growth among other macrophage-specific mechanisms.
Highlights
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb) remains one of the world’s deadliest diseases, killing an estimated 1.5 million people annually [1]
Microdialyser growth curves followed the trend of typical mycobacterial growth: upon inoculation, a typical culture began with a lag period, followed by an exponential growth phase that gave way to a stationary phase
We uncovered an epigenetic rifampicin-resistance phenotype that was dependent on the size of the growth chamber: appearing when the mycobacteria were cultured in the small (200pL) growth chambers and disappearing in the bigger reactor volumes (500pL, 1200pL and 1700pL)
Summary
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb) remains one of the world’s deadliest diseases, killing an estimated 1.5 million people annually [1]. Whereas drugsusceptible forms of the disease are in principle curable, the duration of treatment courses is at least 6 months and may last years [2]. Multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) have poorer and less certain outcomes [2,3,4]. It is expected that shortened antituberculosis treatment regimens will improve patient adherence to treatment, and thereby foster better case management and disease control and minimize the risk of drug resistance [5, 6]. An interesting aspect of long-term chemotherapy in TB is that, whereas more than 95% of the tubercle bacilli population detectable in a patient’s sputum can be cleared in the first few days of treatment, prolonged treatment is required to eradicate the residual minority.
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