Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus

Abstract

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.

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

“…The MICs of the compounds were determined as described previously [26]. Briefly, 100 µL of cation-adjusted Mueller-Hinton (CAMH) and 7H9 broth supplemented with 10% ADC was added to every well of a 96-well microtiter plate.…”

Repositioning rifamycins for Mycobacterium abscessus lung disease

“…Finally, the oxazolidinone linezolid was also reported to synergize with rifabutin [83]. Unfortunately, linezolid's toxicity profile has limited its use in the clinic, but both tedizolid and LCB01-0371 have activity against M. abscessus and improved safety profiles [90,91]. While synergies between these oxazolidinones and rifabutin have not been determined in vitro, rifabutin addition improved the potency of the imipenemtedizolid combination against M. abscessus in a macrophage infection model [92].…”

Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

“…A recent meta-analysis revealed that more than 90% of MDR-TB cases achieved culture conversion after treatment with individualized regimens containing linezolid, underscoring the excellent in vivo efficacy of the drug against MDR-TB (5). Recently, the novel oxazolidinone delpazolid was developed to produce improved antibacterial activity and safety (14,15). In vitro studies and pharmacological evidence have indicated that this new agent is more active than linezolid against various Gram-positive bacteria (14); however, data regarding the in vitro activity of delpazolid against MDR-and XDR-TB are limited.…”