Abstract

Aim Non-tuberculous mycobacteria (NTM) are ubiquitous in the natural environment. Globally, incidence of non-tuberculous mycobacterial disease is on the rise. To date, over 190 species of NTM have been identified, many of which possess inherent natural resistance to antibiotics, developing new drugs is a challenging process with a high risk of failure. The repurposing of existing drugs may be a quick and effective approach. This study investigates the combined effects of bedaquiline (BDQ) and nintedanib (a multi-target tyrosine kinase inhibitor) on NTM, with the aim of providing a novel therapeutic approach against NTM. Methods and Results The number of colony-forming units (CFUs) in macrophages was determined to assess the antibacterial activity of nintedanib against Mycobacterium avium and Mycobacterium abscessus. To evaluate the efficacy of nintedanib in combination with BDQ in a mouse model of pulmonary infection. The mechanism of the synergistic antibacterial effect of nintedanib and BDQ was investigated using assays of immune cells and immune factors, ATP measurement, transcriptomic sequencing and RT-PCR. Nintedanib significantly enhanced the intracellular antibacterial activity of BDQ against M. avium and M. abscessus. In mice infection model, nintedanib enhanced the efficacy of BDQ, reducing the extent of inflammatory damage and fibrosis in the mice’s lung tissue. The mechanism by which nintedanib enhances the antibacterial activity of BDQ is as follows: on the one hand, it boosts adaptive immunity in mice, promoting anti-inflammatory and tissue-repairing immune responses; on the other hand, it enhances BDQ’s ability to inhibit ATP production and disrupts bacterial metabolic pathways. Conclusion In vitro and in vivo studies have shown that nintedanib enhances the antibacterial activity of BDQ, accelerates pathogen clearance and reduces lung damage.