In Vitro Activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis

Abstract

The in vitro activities of DA-7157, a novel oxazolidinone, against clinical isolates of Nocardia brasiliensis and Mycobacterium tuberculosis were determined. Equal MIC 50 s and MIC 90 s (0.25 and 0.5 g/ml, respectively) were found for susceptible and multidrug-resistant isolates of M. tuberculosis. The N. brasiliensis isolates showed an MIC 90 of 1 g/ml and an MIC 50 of 1 g/ml. The DA-7157 prodrug, DA-7218, exhibited similar MICs for M. tuberculosis but fivefold-higher MICs for N. brasiliensis.Oxazolidinones are a new, unique class of synthetic antibacterial agents effective against many gram-positive bacteria, including aerobic pathogenic actinomycetes of the genera Mycobacterium, Nocardia, and Actinomadura (3,7,8,9). Linezolid, the first oxazolidinone on the market, has been proven to be active in animal models (2), as well as in clinical trials with patients infected with Nocardia spp. (5) or Mycobacterium tuberculosis (1). Oxazolidinones selectively inhibit bacterial protein synthesis by binding to bacterial 23S rRNA of the 50S subunit and preventing the formation of a functional 70S initiation complex (6). The antibacterial activity of oxazolidinones depends on the affinity for the site of action on the ribosome; therefore, by modifying their chemical structure, new compounds with improved antimicrobial activity can be obtained.Recently, a new oxazolidinone, DA-7157, was shown to be active in vitro against several gram-positive species, with the observation of a level of activity superior to that of linezolid (K. Lee, J. H. Yum, D. Yong, Y. Chong, S. H. Choi, and J. K. Rhee, Abstr. 45th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1419Chemother., abstr. F- , 2005. The DA-7157 compound is produced by the metabolism of a highly hydrophilic prodrug, DA-7218 (Fig. 1) . The stock solution of DA-7218 was prepared in distilled water. In order to compare our results, we also performed susceptibility assays with linezolid, a drug previously tested in vitro against M. tuberculosis with good results. The latter was obtained from Pharmacia and Upjohn (Kalamazoo, Mich.), and the stock was prepared in 7H9GC broth. All working solutions were diluted in 7H9GC broth to a 2ϫ concentration prior to their addition to the microplates. Dimethyl sulfoxide controls were also run to determine its possible toxicity on the microorganisms.A total of 95 M. tuberculosis isolates were tested, including 8 isolates resistant to isoniazid, 1 isolate resistant to rifampin, and 25 clinical isolates resistant to both isoniazid and rifampin. The susceptibility assays were performed by the proportion method. For controls, we ran M. tuberculosis H37Rv and H37Ra. In order to determine the susceptibilities to linezolid, DA-7157, and DA-7218, the broth microdilution method with Alamar Blue was utilized (8). In brief, mycobacterial suspensions were prepared in 0.04% (vol/vol) Tween 80-0.2% bovine serum albumin so their turbidities equaled a McFarland turbidity standard of 1. Suspensions were further diluted 1:25 in 7H9GC broth. The rest of...

Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis

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The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

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Targeting Antibiotic Resistance

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