Abstract
Mycobacterium abscessus (M. abscessus) causes chronic pulmonary infections. Its resistance to current antimicrobial drugs makes it the most difficult non-tuberculous mycobacteria (NTM) to treat with a treatment success rate of 45.6%. Therefore, there is a need for new therapeutic agents against M. abscessus. We identified 10-DEBC hydrochloride (10-DEBC), a selective AKT inhibitor that exhibits inhibitory activity against M. abscessus. To evaluate the potential of 10-DEBC as a treatment for lung disease caused by M. abscessus, we measured its effectiveness in vitro. We established the intracellular activity of 10-DEBC against M. abscessus in human macrophages and human embryonic cell-derived macrophages (iMACs). 10-DEBC significantly inhibited the growth of wild-type M. abscessus and clinical isolates and clarithromycin (CLR)-resistant M. abscessus strains. 10-DEBC’s drug efficacy did not have cytotoxicity in the infected macrophages. In addition, 10-DEBC operates under anaerobic conditions without replication as well as in the presence of biofilms. The alternative caseum binding assay is a unique tool for evaluating drug efficacy against slow and nonreplicating bacilli in their native caseum media. In the surrogate caseum, the mean undiluted fraction unbound (fu) for 10-DEBC is 5.696. The results of an in vitro study on the activity of M. abscessus suggest that 10-DEBC is a potential new drug for treating M. abscessus infections.
Highlights
non-tuberculous mycobacteria (NTM) is ubiquitous in soil and drinking water sources [1]
Pulmonary disease caused by M. abscessus is common in patients with cystic fibrosis (CF), while disseminated infections occur in immunocompromised patients
We determined whether 10-DEBC retained this potent activity compared with defense mechanism [24,25]. These results indicate that 10-DEBC is effective in vitro against clinical isolates of M. abscessus, including Rough (R) and Smooth (S) colony types. 10the reference and clinically and
Summary
NTM is ubiquitous in soil and drinking water sources [1]. NTM often results in high person-to-person contact rates with pathogens [1,2]. M. abscessus is one of the most common NTMs in pulmonary infections that can cause lung or other diseases in healthy individuals. Pulmonary disease caused by M. abscessus is common in patients with cystic fibrosis (CF), while disseminated infections occur in immunocompromised patients. The alarming fact is that M. abscessus is the most common solitary lung infection, with an average treatment success rate of only 45.6% [15,16]. For patients with chronic lung disease due to NTM, none of the currently available treatments have been proven effective for long-term sputum conversion [15]. Current regimens recommend drug combinations for the treatment of M. abscessus pulmonary infections. It phosphorylates and inactivates components of the apoptotic mechanism, including caspase 9 and BCL2-associated agonist of cell death (BAD). 10-DEBC exhibited activity against M. abscessus, both in vitro and intracellular
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