A Novel Oxazolidinone, Contezolid (MRX-I), Expresses Anti-Mycobacterium abscessus Activity
            <i>In Vitro</i>

Guo, Qi; Xu, Liyun; Tan, F.; Zhang, Yongjie; Fan, Junsheng; Wang, Xinghai; Zhang, Zhemin; Li, Bing; Chu, Haiqing

doi:10.1128/aac.00889-21

Cited by 14 publications

(13 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One hundred and ninety‐four clinical isolates of M. abscessus were obtained from sputum and bronchoalveolar lavage fluid samples of patients with confirmed diagonosis of M. abscessus lung disease during the period from 2012 January to 2017 December, according to the latest guideline of NTM treatment recommendations updated by The American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) in 2020 45–48 . The sources of the 194 clinical specimens were as follows: sputum ( n = 169), bronchoalveolar lavage fluid ( n = 22) and tissue ( n = 3).…”

Section: Methodsmentioning

confidence: 99%

In vitro activity of rifabutin against Mycobacterium abscessus, clinical isolates

Chen

Zhang

Guo

et al. 2022

Clin Exp Pharma Physio

Self Cite

View full text Add to dashboard Cite

The antibiotic options available for Mycobacterium abscessus (M. abscessus) infection are limited and no definitive therapeutic strategies have been formulated.The recent discovery that rifabutin is active against M. abscessus has raised interest in using rifabutin to treat this intractable disease. In this study, we evaluated the in vitro activity of rifabutin against 194 M. abscessus clinical isolates collected during 2012 January to 2017 December. As expected, rifabutin demonstrated considerably lower MICs against M. abscessus, with an MIC 50 of 2 μg/mL and MIC 90 of 4 μg/mL, respectively. Notably, the anti-M.abscessus activity was even stronger among clarithromycin-insusceptible strains. In addition, M. abscessus isolates with a rough morphotype were more sensitive to rifabutin compared with those forming smooth colonies when considered as a whole or in separate subspecies. Results from synergistic experiments revealed that the in vitro activity of rifabutin was significantly enhanced by the addition of amikacin, suggesting a promising strategy for M. abscessus infection combination treatment. Finally, five and three mutation patterns in rpoB and arr, respectively, were identified among the 194 strains through whole genome sequencing. However, none of them conferred rifabutin resistance. Our study is among the first to report the susceptibility of M. abscessus to rifabutin in vitro with a large amount of clinical isolates, suggesting that rifabutin is active, both alone and in combination, against M. abscessus and is worth considering as part of a combination treatment regimen for M. abscessus infections.

show abstract

Section: Methodsmentioning

confidence: 99%

In vitro activity of rifabutin against Mycobacterium abscessus, clinical isolates

Chen

Zhang

Guo

et al. 2022

Clin Exp Pharma Physio

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are several novel drug approaches, however, that are currently being investigated. Guo et al have recently shown in vitro efficacy of Cotezolid (MRX-I), (S)-5-([isoxazol-3-ylamino]methyl)-3-(2,3,5-trifluoro-4-[4-oxo-3,4-dihydropyridin-1(2H)-yl]phenyl)oxazolidin-2-one, which is an oxazolidinone, against M. abscessus [ 136 ]. Linezolid, also an oxazolidinone, is recommended for use against M. abscessus ; however, Cotezolid may have an advantage by inducing fewer side effects; oral MRX-I administration was found to be well tolerated in humans in a Phase 1 study where adverse events were shown to be mild to moderate [ 137 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

“…Linezolid, also an oxazolidinone, is recommended for use against M. abscessus ; however, Cotezolid may have an advantage by inducing fewer side effects; oral MRX-I administration was found to be well tolerated in humans in a Phase 1 study where adverse events were shown to be mild to moderate [ 137 ]. In the study by Guo et al, both Cotezolid (MRX-I) and linezolid are effective against M. abscessus but not M. avium or M. intracellulare [ 136 ]. Furthermore, Contezolid (MRX-I) was compatible with other M. abscessus drugs, including Azithromycin, Clarithromycin, Cefoxitin, Imipenum, Tigecycline, Bedaquiline, Amikacin, and Amoxifloxacin [ 136 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

“…In the study by Guo et al, both Cotezolid (MRX-I) and linezolid are effective against M. abscessus but not M. avium or M. intracellulare [ 136 ]. Furthermore, Contezolid (MRX-I) was compatible with other M. abscessus drugs, including Azithromycin, Clarithromycin, Cefoxitin, Imipenum, Tigecycline, Bedaquiline, Amikacin, and Amoxifloxacin [ 136 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

“…one, which is an oxazolidinone, against M. abscessus [136]. Linezolid, also an oxazolidinone, is recommended for use against M. abscessus; however, Cotezolid may have an advantage by inducing fewer side effects; oral MRX-I administration was found to be well tolerated in humans in a Phase 1 study where adverse events were shown to be mild to moderate [137].…”

Section: Guo Et Al Have Recently Shown In Vitro Efficacy Of Cotezolid...mentioning

confidence: 99%

See 2 more Smart Citations

Mycobacterium abscessus: It’s Complex

et al. 2022

View full text Add to dashboard Cite

Mycobacterium abscessus (M. abscessus) is an opportunistic pathogen usually colonizing abnormal lung airways and is often seen in patients with cystic fibrosis. Currently, there is no vaccine available for M. abscessus in clinical development. The treatment of M. abscessus-related pulmonary diseases is peculiar due to intrinsic resistance to several commonly used antibiotics. The development of either prophylactic or therapeutic interventions for M. abscessus pulmonary infections is hindered by the absence of an adequate experimental animal model. In this review, we outline the critical elements related to M. abscessus virulence mechanisms, host–pathogen interactions, and treatment challenges associated with M. abscessus pulmonary infections. The challenges of effectively combating this pathogen include developing appropriate preclinical animal models of infection, developing proper diagnostics, and designing novel strategies for treating drug-resistant M. abscessus.

show abstract

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Wang,

Li,

Gordeev

et al. 2024

J of Applied Toxicology

View full text Add to dashboard Cite

Contezolid acefosamil (CZA) is an intravenous prodrug of oxazolidinone antibiotic contezolid (CZD). It is being developed to treat infections due to Gram‐positive bacteria including multidrug‐resistant pathogens, while addressing myelosuppression and neurotoxicity limitations associated with long‐term use of this class of antibiotics. In vivo, CZA is rapidly deacylated into its first metabolite MRX‐1352, which is then dephosphorylated to release active drug CZD. Four‐week repeat‐dose toxicity studies of intravenous CZA were conducted in Sprague–Dawley rats (40, 80, and 160/120 mg/kg/dose twice a day [BID]) and beagle dogs (25, 50, and 100/75 mg/kg/dose BID). The high doses administered to both rats and dogs were adjusted due to adverse effects including decreased body weight and food consumption. Additionally, a dose‐dependent transient reduction in erythrocyte levels was recorded at the end of dosing phase. Importantly, no myelosuppressive reduction in platelet counts was observed, in contrast to the myelosuppression documented for standard‐of‐care oxazolidinone linezolid. The no‐observed‐adverse‐effect level (NOAEL) of CZA was 80 and 25 mg/kg/dose BID in rats and dogs, respectively. Separately, 3‐month neuropathological evaluation in Long–Evans rats (25, 37.5, and 50 mg/kg/dose, oral CZA, BID) demonstrated no neurotoxicity in the central, peripheral, and optical neurological systems. Toxicokinetic data from these studies revealed that CZD exposures at NOAELs were higher than or comparable with that for the intended clinical dose. These results confirm the favorable safety profile for CZA and support its clinical evaluation for long‐term therapy of persistent Gram‐positive infections, beyond the application for earlier oxazolidinones.

show abstract

A Novel Oxazolidinone, Contezolid (MRX-I), Expresses Anti-Mycobacterium abscessus Activity In Vitro

Cited by 14 publications

References 16 publications

In vitro activity of rifabutin against Mycobacterium abscessus, clinical isolates

In vitro activity of rifabutin against Mycobacterium abscessus, clinical isolates

Mycobacterium abscessus: It’s Complex

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Contact Info

Product

Resources

About