The Clinical-stage Drug BTZ-043 Accumulates in Murine Tuberculosis Lesions and Efficiently Acts Against Mycobacterium Tuberculosis

Overview

Journal Nat Commun

Date 2025 Jan 18

PMID 39827265

Authors

Andreas Rompp

Axel Treu

Julia Kokesch-Himmelreich

Franziska Marwitz

Julia Dreisbach

Nadine Aboutara

Doris Hillemann

Moritz Garrelts

Paul J Converse

Sandeep Tyagi

Sina Gerbach

Luzia Gyr

Ann-Kathrin Lemm

Johanna Volz

Alexandra Holscher

Leon Groschel

Eva-Maria Stemp

Norbert Heinrich

Florian Kloss

Eric L Nuermberger

Dominik Schwudke

Michael Hoelscher

Christoph Holscher

Kerstin Walter

Affiliations

Soon will be listed here.

Abstract

The development of granulomas with central necrosis harboring Mycobacterium tuberculosis (Mtb) is the hallmark of human tuberculosis (TB). New anti-TB therapies need to effectively penetrate the cellular and necrotic compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ-043 is a novel antibiotic showing good bactericidal activity in humans in a phase IIa trial. Here, we report on lesional BTZ-043 concentrations severalfold above the minimal-inhibitory-concentration and the substantial local efficacy of BTZ-043 in interleukin-13-overexpressing mice, which mimic human TB pathology of granuloma necrosis. High-resolution MALDI imaging further reveals that BTZ-043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center. This is the first study that visualizes an efficient penetration and accumulation of a clinical-stage TB drug in human-like centrally necrotizing granulomas and that also determines its lesional activity. Our results most likely predict a substantial bactericidal effect of BTZ-043 at these hard-to-reach sites in TB patients.

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