Back to search

BEDREHELSE-Bedre helse og livskvalitet

Drug targeting for improved treatment of multi drug resistant tuberculosis.

Alternative title: NANO-MDR-TB

Awarded: NOK 8.0 mill.

Tuberculosis, caused by Mycobacterium tuberculosis remains the most serious bacterial disease of humans. Until about ten years ago the same cocktail of four antibiotics had been used for 50 years to treat TB. This combination worked but it is highly toxic to patients, it needs at least 6 months treatment and the development of multi-drug resistance is a growing problem for this disease, the most lethal infectious disease of humans. Until around 2005 new drugs were ineffective but around that time two powerful new drugs were synthesized that looked highly promising in clinical trials, namely pretomanid and bedaquiline. These were the first TB drugs to be clinically approved for over 50 years and they possess promising effects in the laboratory against multi drug resistant strains of M.tuberculosis. Since 2010 the Griffiths group has been following the hypothesis that the efficacy of drugs in general can be improved, and side-effects reduced, by encapsulating them inside minute nanoparticles that can at least in part be targeted to the disease site. Currently most animal studies are carried out in mouse models, a problem since it is difficult to visualize nanoparticles inside an opaque animal. For this reason in 2010 we introduced the transparent zebrafish embryo as a better model to follow the fate of injected nanoparticles and the cells they interact with. These fish are infected with Mycobacterium marinum, the fish TB organism that from sequence analysis is closely related to M.tuberculosis. We successfully established a strong international consortium whereby Andrew Thompson in New Zealand synthesized new derivatives of pretomanid that were then sent for encapsulation in the small beads to Matthias Barz (Mainz, Germany); these drugs of the pretomanid family had been tested in New Zealand against M.tuberculosis in vitro and all were more potent than the parental compound. The nanoparticles are then sent to our group for testing for their toxicity and efficacy against the fish TB. Around ten compounds have been tested in detail and one drug has been especially potent (drug D) in protecting the zebrafish against TB. This drug D nanoparticle was then tested against mice infected with M.tuberculosis by Ulrich Schaible in Borstel Germany and found to combine low toxicity with effective therapy. The paper describing this work was well received and is now in revision for publication in a high-ranking nanoparticle journal ACS Nano. A side project that emerged from this project is based on the growing realization that the TB granuloma (the diseased tissue where most bacteria reside) shares many functional features with tumours that form during cancer. Federico Fenaroli funded by this project supervised a Masters student Agnes Kocere who developed a cancer model based on injected mouse cancer cells into the zebrafish. A cancer chemotherapy drug was put into nanoparticles by Bruno De Geest (Ghent, Belgium) and shown to be highly effective in treating the fish. Such experiments are normally done in mouse models but it is far easier to follow the nanoparticles in the transparent zebrafish. This study was published in EBioMedicine. This strategy also greatly reduces the need to kill mice, that makes the fish ethically more acceptable to the community.

Outcomes: 1. Establishment of international expert multi-disciplinary research collaboration that included three international network meetings. 2. Impact: 1. Development of promising nanoparticle formulation that encapsulates a new derivative of the pretomanid against tuberculosis. 2. Establishment of the zebrafish as a better screening animal for nanoparticles than mouse due to its improved imaging capabilities. 3. A reduction in use of mice in agreement with international animal use ethical goals.

Multi-drug resistant (MDR) TB is a global public health issue. It requires treatment for over 2 years with extremely toxic drugs. These agents need smarter drug delivery systems to minimize their toxic effects and shorten treatment regimens. Incorporating drugs into nanoparticles (NP) can target host cells (macrophages) that then assemble into granulomas, where Mtb hides from the immune system. Such NP can overcome low antibiotic permeability into TB granulomas. Experience from cancer chemotherapy shows that NP targeting enhances drug efficacy and reduces toxicity towards non-target cells. This proposal combines an Oslo group developing NP for injection and an Indian group focused on TB inhalation therapy using larger microparticles (MP). A New Zealand group specializing in derivatives of the new MDR-TB drug PA-824 and two NP specialist groups in Germany and Belgium will give crucial support. We propose a hierarchical strategy to make and evaluate NP/MP containing derivatives of PA-824 that exhibit higher potency but low oral bioavailability. Three other MDR-TB drugs will also be tested. NP containing drugs will first be tested in Mtb-infected macrophages. Promising NP/MP will be evaluated in the zebrafish embryo model of granulomatous TB that allows bacteria, NP and host cells to be seen together in real time at high resolution. Little is known about dynamic cellular interaction within granulomas. The zebrafish model can address biodistribution and toxicity of drug-containing NP rapidly and inexpensively, as an optimal intermediate screen between the cellular and mammalian models. It can generate proof-of-concept of enhanced efficacy through NP targeting. NP that show safe and efficient targeting in zebrafish will be tested in the aerosol infection mouse model of TB, to generate data required for regulatory approval. Our multi-disciplinary strategy provides a rational foundation for enabling preclinical development of novel delivery systems for MDR TB.

Publications from Cristin

No publications found

No publications found

No publications found

No publications found

Funding scheme:

BEDREHELSE-Bedre helse og livskvalitet