16.02.2024
New active ingredient for the treatment of tuberculosis
A recent clinical study shows that ganfeborole could be a promising candidate for the safe and effective treatment of pulmonary tuberculosis. Using microbiological testing and innovative imaging techniques, an international research team was able to prove the efficacy of this novel agent and pave the way for further clinical trials. The results have now been published in the renowned journal Nature Medicine.
The increase in drug resistance is making the treatment of tuberculosis, the most common fatal bacterial infectious disease worldwide, even more difficult. According to the World Health Organization (WHO), only 60% of patients with multidrug-resistant tuberculosis are successfully treated worldwide. In recent years, strains of tuberculosis that are resistant to all available drugs have also become increasingly common. New drugs are therefore urgently needed.
Before new candidate drugs can be approved for the treatment of tuberculosis patients, they must undergo a series of development phases in clinical trials. An important step is the documentation of the so-called early bactericidal activity (EBA), in which the efficacy of a drug candidate is tested on tuberculosis patients in a 14-day monotherapy. If a drug shows sufficient early bactericidal activity, it is tested in more extensive clinical trials to investigate its efficacy, safety and effectiveness in the treatment of patients.
The Clinical Tuberculosis Unit (ClinTB) of the German Center for Infection Research (DZIF) at the Research Center Borstel, Leibniz Lung Center has been involved in conducting EBA studies for 10 years as a partner. Together with international colleagues, the researchers have now been able to show that the novel active substance ganfeborole exhibits clinical activity in patients.
Ganfeborole belongs to a new class of antibiotics, the so-called "leucyl-tRNA synthetase inhibitors", which prevent the formation of new important proteins in bacteria and thus inhibit the growth of pathogens.
In addition to microbiological investigations into the effectiveness of Ganfeborol on the growth of tuberculosis bacteria, this study was the first to compare innovative imaging methods, so-called PET/CTs. With this method, which has been used successfully in tumor diagnostics, even minimal inflammation and cell changes caused by the bacteria can be made visible.
The results of the PET/CTs were compared with extensive molecular biological investigations of copies of the genetic material of tuberculosis patients in their blood, so-called RNAs. "Using RNA analysis, we discovered an association between the activity of a certain cell population in the human body and the dosage of Ganfeboron. This correlation is also found in the PET/CT analysis data. Our results explain how changes in the imaging of pneumonia in tuberculosis are caused by the influence of drugs on metabolic activity," says Maja Reimann from the DZIF Clinical Tuberculosis Unit in Borstel. The method used here enabled the effectiveness of the drug on the lung tissue to be visualized at an early stage and could in future be an important tool in the clinical testing of new active substances and in the development of biomarkers.
The efficacy and tolerability of Ganfeborol will now be investigated in the next stage of clinical trials. In the PARADIGM4TB study, in which the Borstel team is participating, patients in Asia, Europe, Africa and South America are receiving Ganfeborol in combination with other antibiotics in order to determine the best combination for treating tuberculosis.
Publication:
Diacon AH, Barry III CE, Carlton A, Chen RY, Davies M, de Jager V, Fletcher K, Koh GCKW, Kontsevaya I, Heyckendorf J, Lange C, Reimann M, Penman SL, Scott R, Maher-Edwards G, Tiberi S, Vlasakakis G, Upton CM, Barros Aguirre D. Fourteen-day treatment responses in participants with rifampicin-susceptible pulmonary tuberculosis receiving the leucyl-tRNA synthetase inhibitor GSK3036656: a phase 2a open-label, randomized trial. Nat Med 2024, doi: 10.1038/s41591-024-02829-7
Contact:
Dr. Maja Reimann
DZIF Infrastruktur ClinTB
Forschungsgruppe Klinische Infektiologie
Forschungszentrum Borstel, Leibniz Lungenzentrum
Parkallee 35
23845 Borstel
Phone: 04537 188 3678
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