In Vitro Activities of the Novel Oxazolidinones DA-7867 and DA-7157 against Rapidly and Slowly Growing Mycobacteria

Vera-Cabrera, Lucio; Brown‐Elliott, Barbara A.; Wallace, Richard J.; Ocampo‐Candiani, Jorge; Welsh, Oliverio; Choi, Sun Jin; Molina-Torres, Carmen A.

doi:10.1128/aac.00763-06

Cited by 31 publications

(21 citation statements)

References 17 publications

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“…In the present study, linezolid demonstrated similar activities against most mycobacterial isolates in agreement with previous reports (5,6). However, the M. avium complex and M. abscessus required 32 mg/L to inhibit 90z of the isolates tested, indicating that treatment with linezolid against these two species is difficult.…”

supporting

confidence: 80%

“…In the second-line drugs, the highest drug resistance rate was to PAS (91.5z), followed by ofloxacin (69.2z), while the lowest resistant rates were for amikacin and capreomycin. Linezolid showed excellent activity against M. kansasii, and M. fortuitum, with MIC ranges of 0.5-1 mg/L and 0.5-8 mg/L, respectively, which was in accordance with previous reports (5,6). Similarly, the in vitro activities of sy142 and sy144 against these two species were comparable to those of linezolid.…”

supporting

confidence: 78%

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Evaluation of the Efficacy of Novel Oxazolidinone Analogues against Nontuberculous Mycobacteria In Vitro

et al. 2015

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SUMMARY: Nontuberculous mycobacteria (NTM) are associated with a number of clinical diseases and only a few antitubercular agents are active against them. Oxazolidinones comprise a novel class of antimicrobials that inhibit bacterial protein synthesis at the ribosome. Linezolid, the first oxazolidinone antibacterial agent approved for clinical use, has excellent activity against some NTM but is ineffective against others. Sy142 and sy144 are novel oxazolidinones with demonstrated activties against Mycobacterium tuberculosis and Staphylococcus aureus. In this work, we compared the susceptibilities of key NTM species to linezolid, sy142, and sy144. The organisms included 21 isolates of Mycobacterium abscessus, 31 of Mycobacterium avium, 11 of Mycobacterium chelonae, 24 of Mycobacterium fortuitum, 26 of Mycobacterium kansasii, and 17 of Mycobacterium intracellulare. For M. kansasii and M. fortuitum, linezolid showed excellent antimicrobial activity, and an equal MIC range was found in sy142 and sy144. For the species that linezolid was less active against, sy142 and sy144 showed greater antimicrobial activities or exhibited equal compared to linezolid. Particularly, for M. avium and M. intracellulare, the in vitro antimicrobial activity of sy142 was 4-fold higher than that of linezolid. These results demonstrate the potential of these compounds to treat NTM infections.

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confidence: 80%

supporting

confidence: 78%

Evaluation of the Efficacy of Novel Oxazolidinone Analogues against Nontuberculous Mycobacteria In Vitro

et al. 2015

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“…bolletii (MIC of 0.12 g/ml for TZD compared with 0.5 g/ml for LZD). The 2006 study also reported 17 isolates of M. chelonae complex, but again the species were not differentiated (i.e., M. chelonae and M. immunogenum) as in this study (5).…”

Section: Discussionmentioning

confidence: 76%

“…Additionally, the 2006 study showed a single isolate of M. terrae complex (not identified to the species level) with a TZD MIC of 1 g/ml compared with 16 g/ml with LZD (5). Six isolates of M. simiae in the 2006 study exhibited a TZD MIC range of 1 to 8 g/ml and an LZD MIC range of 8 to 32 g/ml (MIC 50 s were not given [5]) compared with the TZD MIC range of 1 to Ͼ32 g/ml (MIC 50 , 8 g/ml) and an LZD MIC range of 8 to 128 g/ml (MIC 50 , 64) of eight isolates in this study.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

Brown‐Elliott

Wallace

2017

J Clin Microbiol

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Tedizolid is a new oxazolidinone with improved in vitro and intracellular potency against Mycobacterium tuberculosis, including multidrug-resistant strains, and some species of nontuberculous mycobacteria (NTM) compared with that of linezolid. Using the current Clinical and Laboratory Standards Institute (CLSI)-recommended method of broth microdilution, susceptibility testing of 170 isolates of rapidly growing mycobacteria showed equivalent or lower (1-to 8-fold) MIC 50 and/or MIC 90 values for tedizolid compared with that for linezolid. The tedizolid MIC 90 values for 81 isolates of M. abscessus subsp. abscessus and 12 isolates of M. abscessus subsp. massiliense were 8 g/ml and 4 g/ml, respectively, compared with linezolid MIC 90 values of 32 g/ml for both. The MIC 90 values for 20 isolates of M. fortuitum were 2 g/ml for tedizolid and 4 g/ml for linezolid. Twenty-two isolates of M. chelonae had tedizolid and linezolid MIC 90 s of 2 g/ml and 16 g/ml, respectively. One hundred forty-two slowly growing NTM, including 7/7 M. marinum, 7/7 M. kansasii, and 7/11 of other less commonly isolated species, had tedizolid MICs of Յ1 g/ml and linezolid MICs of Յ4 g/ml. One hundred isolates of Mycobacterium avium complex and eight M. simiae isolates had tedizolid MIC 50 s of 8 g/ml and linezolid MIC 50 s 32 and 64 g/ml, respectively. Nine M. arupense isolates had MIC 50 s of 4 g/ml and 16 g/ml for tedizolid and linezolid, respectively. These findings demonstrate a greater in vitro potency of tedizolid than linezolid against NTM and suggest that an evaluation of tedizolid as a potential treatment agent for infections caused by selected NTM is warranted.KEYWORDS oxazolidinones, susceptibility testing, tedizolid N ontuberculous mycobacteria (NTM) are responsible for a multiplicity of different types of infections, including respiratory, cutaneous, and systemic infections. Many species of NTM are multidrug resistant (1), emphasizing the urgent need for new antimicrobials with efficacies against these organisms.Tedizolid phosphate is a novel oxazolidinone prodrug (TR-701) that is transformed in the serum into the active drug, tedizolid ([TZD] TR-700, formerly DA-7157) (2) with a broad range of activities against Gram-positive microorganisms, including mycobacteria. The mechanism of action of TZD is by the inhibition of protein synthesis. TZD binds to the 50S ribosome, apparently at a site near the 30S ribosome, which blocks the formation of the 70S initiation complex and, in turn, prevents protein synthesis (3). The supposition is that the major site of action of oxazolidinones is at the ribosomal peptidyltransferase center, and this unique mechanism of action eliminates the likelihood of cross-resistance with other antimicrobial classes (3).Previous reports of in vitro and in vivo (intracellular) activities against Mycobacterium tuberculosis, including multidrug-resistant strains (4), and Nocardia brasiliensis have been published (5-7). A previously published study by Vera-Cabrera et al. showed in vitro activities of TZ...

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Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

Egorova¹,

Jackson

Gavrilyuk³

et al. 2021

Medicinal Research Reviews

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The Mycobacterium abscessus complex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successful M. abscessus pulmonary infection therapy, and existing drug regimens recommended by the British or the American Thoracic Societies are associated with poor clinical outcomes. Therefore, novel antibacterial drugs are urgently needed to contain this global threat. The current anti‐M. abscessus small‐molecule drug development process can be enhanced by two parallel strategies—discovery of compounds from new chemical classes and commercial drug repurposing. This review focuses on recent advances in the finding of novel small‐molecule agents, and more particularly focuses on the activity, mode of action and structure–activity relationship of promising inhibitors from five different chemical classes—benzimidazoles, indole‐2‐carboxamides, benzothiazoles, 4‐piperidinoles, and oxazolidionones. We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest in M. abscessus that may be worthy of future drug and adjunct therapeutic development.

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In Vitro Activities of the Novel Oxazolidinones DA-7867 and DA-7157 against Rapidly and Slowly Growing Mycobacteria

Cited by 31 publications

References 17 publications

Evaluation of the Efficacy of Novel Oxazolidinone Analogues against Nontuberculous Mycobacteria In Vitro

Evaluation of the Efficacy of Novel Oxazolidinone Analogues against Nontuberculous Mycobacteria In Vitro

In Vitro Susceptibility Testing of Tedizolid against Nontuberculous Mycobacteria

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

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