Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.
Tuberculosis kills more people worldwide than any other infectious disease. Treatment requires multiple drug therapy administered over long periods (6-24 months). The emergence of multidrug-resistant strains is a major problem, and with few new drugs in the pipeline, a novel modus operandi is urgently required. Solid drug nanoparticles (SDNs), a new development in nanomedicine, offer a fresh therapeutic approach. Here, we show that SDNs are more effective (50-fold) at killing pathogenic mycobacteria than aqueous forms of the same drug and can target mycobacteria internalised by macrophages, where bacilli reside. We demonstrate synthesis of dual and triple drug loaded SDNs, facilitating combination tuberculosis therapy. Our results suggest that by employing SDNs of existing antibiotics, it may be possible to improve drug delivery and therefore reduce drug dosage to lessen side effects and fight drug resistance.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), causes the most human deaths than any other diseases from a single infectious agent. Treatments are long and costly and have many associated side effects. Intracellular bacilli are slow growing and difficult to target, which is augmenting the emergence of multi-drug resistance. A hallmark trait of TB is the formation of granulomas, chronic cellular aggregates, which limit bacterial growth but provides a survival reservoir where bacilli may disseminate from. Targeting intracellular Mtb is challenging, but nanomedicine may offer a solution. Nanomedicine is a significantly growing research area and offers the potential for specific disease targeting, dosage reduction, and intracellular drug delivery. This review discusses the application of the various forms of nanomedicine towards targeting of Mtb.
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