Tuberculosis bacteria hiding in dead lung tissue can be treated by novel antibiotic

Around 10 million people contract tuberculosis (TB) annually – the disease caused by the Mycobacterium tuberculosis (Mtb) – with it then killing approximately 1.5 million patients each year. Currently, to be treated effectively, requires several months taking a combination of antibiotics. However, the evolution of multi-drug-resistant strains of TB has spurred the need for research into alternative therapies.

A novel antibiotic – BTZ-043 – has been jointly developed by researchers from the German Centre for Infection Research (DZIF), the Institute for Infectious Diseases and Tropical Medicine at the LMU University Hospital Munich (TIM) and the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (LHKI) in Jena, eastern Germany, and has shown strong potency against bacteria.

In a recent study DZIF scientists led by the University of Bayreuth and the Research Centre Borstel, Leibniz Lung Centre – in collaboration with LHKI, the TIM and Johns Hopkins University, Maryland, USA – have been able to show that BTZ-043 is effective in penetrating TB lesions and accumulates there in high concentrations. The drug candidate has been shown to be effective against the mycobacteria in this context.

A characteristic feature of tuberculosis is the formation of nodules called granulomas. This nodular tissue forms in the wall of the effected lung and often contain Mtb. Granulomas are composed of a fibrous capsule which surrounds a layer of immune cells and a core of dead tissue – the necrotic core – where Mtb can ‘hide’ and survive. Given necrotic areas have poor blood supply they have posed a particular challenge to treat as it is usually difficult for antibiotics to reach them.

Using a mouse model that reflects the TB pathology of granuloma necrosis in humans, the DZIF research team has demonstrated the remarkable ability of BTZ-043 to efficiently penetrate, accumulate and reduce the bacterial load in these necrotic granulomas.

The researchers exploited an advanced mouse model in which a genetic modification causes the development of granulomas in these animals similar to those found in human TB patients. The researchers have demonstrated that the concentration of BTZ-043 in the lesions was many times higher than the minimum concentration required to effectively combat Mtb.

High-resolution MALDI mass spectrometry also revealed the ability of BTZ-043 to penetrate deep into the cellular compartments of the lesions and their necrotic centres.

“Our study represents an important step in the development of new tuberculosis antibiotics, as we were able – for the first time – to visualise the distribution of a clinical-stage TB drug [that was] under development [while present] in the granuloma,” said Professor Andreas Römpp from the University of Bayreuth, chair of bioanalytical sciences and food analysis, a DZIF scientist and a corresponding author of the study.

“The ability of BTZ-043 to accumulate and act in these hard-to-reach lesions indicates a strong bactericidal effect that could make tuberculosis therapy more efficient,” adds Dr. Kerstin Walter from the Research Centre Borstel, Leibniz Lung Centre a corresponding author and DZIF scientist.

This advanced mouse model – unlike many other commonly-used research mouse models – reproduces the pathology of human TB very well.

“It is a milestone in the search for new antibiotics against tuberculosis,” added Dr. Christoph Hölscher, research group leader at the Research Centre Borstel, Leibniz Lung Centre.

“These findings are promising for the millions of people suffering from tuberculosis worldwide and offer a glimpse of a future in which less accessible TB lesions can be reached [by using] another drug,” said Dr. Julia Dreisbach, Scientific Program Manager for BTZ-043 at the TIM.

“As research progresses, the potential of BTZ-043 to improve clinical outcomes for tuberculosis patients becomes clearer,” she added.

The research was funded by the German Federal Ministry of Education and Research (BMBF) in the framework of the DZIF.

For further reading please visit: https://doi.org/10.1038/s41467-025-56146-9