Mycobacterium abscessus is a highly pathogenic drug-resistant rapidly growing mycobacterium. In this study, we evaluated the in vitro , intracellular, and in vivo activities of LCB01-0371, a novel and safe oxazolidinone derivative, for the treatment of M. abscessus infection and compared its resistance to that of other oxazolidinone drugs. LCB01-0371 was effective against several M. abscessus strains in vitro and in a macrophage model of infection. In the murine model, a similar efficacy to linezolid was achieved, especially in the lungs. We induced laboratory-generated resistance to LCB01-0371; sequencing analysis revealed mutations in rplC of T424C and G419A and a nucleotide insertion at the 503 position. Furthermore, LCB01-0371 inhibited the growth of amikacin-, cefoxitin-, and clarithromycin-resistant strains. Collectively, our data indicate that LCB01-0371 might represent a promising new class of oxazolidinones with improved safety, which may replace linezolid for the treatment of M. abscessus .

Mycobacterium abscessus, a leading cause of severe lung infections in immunocompromised individuals, poses significant challenges for current therapeutic strategies due to resistance mechanisms. Therefore, understanding the intrinsic and acquired antibiotic resistance of M. abscessus is crucial for effective treatment. This review highlights the mechanisms employed by M. abscessus to sustain antibiotic resistance, encompassing not only conventional drugs but also newly discovered drug candidates. This comprehensive analysis aims to identify novel entities capable of overcoming the notorious resistance exhibited by M. abscessus, providing insights for the development of more effective therapeutic interventions.

A novel oxazolidinone with cyclic amidrazone, delpazolid (LCB01-0371), was synthesized by LegoChem BioSciences, Inc. (Daejeon, Korea). Delpazolid can improve the minimum bactericidal concentration of Mycobacterium tuberculosis H37Rv and significantly reduce resistance rates, especially of multi-drug-resistant tuberculosis (MDR-TB) isolates, compared with linezolid. Therefore, delpazolid can be used to treat MDR-TB. The safety, tolerability, and pharmacokinetics of delpazolid have been evaluated in a phase 1 clinical trial, which revealed that it does not cause adverse events such as myelosuppression even after three weeks of repeated dosing. Interim efficacy and safety results, particularly those from a clinical phase 2a early bactericidal activity trial including patients with drug-susceptible tuberculosis, were reported and the findings will be further analyzed to guide phase 2a studies.

Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, there have only been a few new compounds or drug formulations which are active against M. abscessus, and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-M. abscessus medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against M. abscessus rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for M. abscessus therapy. For further validation, epetraborole showed significant activity against the growth of the M. abscessus wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of M. abscessus that reside in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of epetraborole in the zebrafish infection model was greater than that of tigecycline. Thus, we concluded that epetraborole is a potential anti-M. abscessus candidate in the M. abscessus drug search.

Mycobacterium abscessus is a rapid-growing, multidrug-resistant, non-tuberculous mycobacterial species responsible for a variety of human infections, such as cutaneous and pulmonary infections. M. abscessus infections are very difficult to eradicate due to the natural and acquired multidrug resistance profiles of M. abscessus. Thus, there is an urgent need for the development of effective drugs or regimens against M. abscessus infections. Here, we report the activity of a US Food and Drug Administration approved drug, thiostrepton, against M. abscessus. We found that thiostrepton significantly inhibited the growth of M. abscessus wild-type strains, subspecies, clinical isolates, and drug-resistant mutants in vitro and in macrophages. In addition, treatment of macrophages with thiostrepton significantly decreased proinflammatory cytokine production in a dose-dependent manner, suggesting an inhibitory effect of thiostrepton on inflammation induced during M. abscessus infection. We further showed that thiostrepton exhibits antimicrobial effects in vivo using a zebrafish model of M. abscessus infection.