There has been a marked increase in drug-resistant tuberculosis in New York City. Previously treated patients, those infected with HIV, and injection-drug users are at increased risk for drug resistance. Measures to control and prevent drug-resistant tuberculosis are urgently needed.
Multidrug-resistant tuberculosis is readily transmitted among hospitalized patients with AIDS. Physicians must be alert to this danger and must enforce adherence to the measures recommended to prevent nosocomial transmission of tuberculosis.
Oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. U-100592 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and U-100766 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide are novel oxazolidinone analogs from a directed chemical modification program. MICs were determined for a variety of bacterial clinical isolates; the respective MICs of U-100592 and U-100766 at which 90% of isolates are inhibited were as follows: methicillin-susceptible Staphylococcus aureus, 4 and 4 micrograms/ml; methicillin-resistant S. aureus, 4 and 4 micrograms/ml; methicillin-susceptible Staphylococcus epidermidis, 2 and 2 micrograms/ml; methicillin-resistant S. epidermidis, 1 and 2 micrograms/ml; Enterococcus faecalis, 2 and 4 micrograms/ml; Enterococcus faecium, 2 and 4 micrograms/ml; Streptococcus pyogenes, 1 and 2 micrograms/ml; Streptococcus pneumoniae, 0.50 and 1 microgram/ml; Corynebacterium spp., 0.50 and 0.50 micrograms/ml; Moraxella catarrhalis, 4 and 4 micrograms/ml; Listeria monocytogenes, 8 and 2 micrograms/ml; and Bacteroides fragilis, 16 and 4 micrograms/ml. Most strains of Mycobacterium tuberculosis and the gram-positive anaerobes were inhibited in the range of 0.50 to 2 micrograms/ml. Enterococcal strains resistant to vancomycin (VanA, VanB, and VanC resistance phenotypes), pneumococcal strains resistant to penicillin, and M. tuberculosis strains resistant to common antitubercular agents (isoniazid, streptomycin, rifampin, ethionamide, and ethambutol) were not cross-resistant to the oxazolidinones. The presence of 10, 20, and 40% pooled human serum did not affect the antibacterial activities of the oxazolidinones. Time-kill studies demonstrated a bacteriostatic effect of the analogs against staphylococci and enterococci but a bactericidal effect against streptococci. The spontaneous mutation frequencies of S. aureus ATCC 29213 were <3.8 x 10(-10) and <8 x 10(-11) for U-100592 and U-100766, respectively. Serial transfer of three staphylococcal and two enterococcal strains on drug gradient plates produced no evidence of rapid resistance development. Thus, these new oxazolidinone analogs demonstrated in vitro antibacterial activities against a variety of clinically important human pathogens.
Ethambutol at 3.0 ,ug/ml inhibited the transfer of label from D- ['4C]glucose into the D-arabinose residue of arabinogalactan in whole cells of a drug-susceptible strain of Mycobacterium smegmatis. This inhibition began almost immediately after exposure of the cells to the drug. When drug-resistant M. smegmatis was used in a similar experiment, no such drug inhibition was detected. A much higher concentration of ethambutol (>50 ,ug/ml) was required to show this inhibition. The drug also inhibited synthesis of arabinose-containing oligosaccharides when a cell-free enzyme system was used. These results suggest that the site of action of ethambutol is somewhere on the pathway between the conversion of D-glucose to D-arabinose and the transfer of arabinose into arabinogalactan. The primary mode of action of ethambutol appears to be inhibition of arabinogalactan synthesis.Ethambutol is an effective and very specific drug used in combination with isoniazid to treat tuberculosis (8,9,17,18 smegmatis were used in this study (10). The ethambutolsusceptible M. smegmatis was an in-house strain of the Mycobacteriology Laboratory, Centers for Disease Control, Atlanta, Ga., and the ethambutol-resistant mutant was derived from this parent susceptible strain. The cells used to prepare cell extracts and to isolate the arabinogalactan and arabinomannan were grown in glycerol-alanine-salts medium (16) in a 28-liter New Brunswick fermentor (New Brunswick Scientific Co., Inc., Edison, N.J.) at 37°C for 24 h. Cells of M. smegmatis used to determine the in vivo synthesis of polysaccharides were grown in supplemented Middlebrook 7H9 broth (Difco Laboratories, Detroit, Mich.) at 37°C with shaking (11) to an A650 of 0.05 (ca. 2.5 x 106 CFU/ml). The albumin-dextrose enrichment was omitted, and 0.2% glycerol and 0.05% Tween 80 (Sigma Chemical Co., St. Louis, Mo.) were substituted.Preparation of cell-free enzyme system for synthesis of arabinose-containing oligosaccharides. Harvested cells of drug-susceptible M. smegmatis (25 g, wet weight) were suspended in 25 ml of 0.05 M potassium phosphate buffer, pH 7.0, and sonicated at full power in a Branson sonifier at 0 to 10°C for 7 min. The suspension was centrifuged at 10,000 x g for 30 min, and the turbid supernatant was recovered. This supernatant was recentrifuged under the same conditions as before to yield the 10,000 x g supernatant fraction. This preparation, containing about 43 mg of protein per ml as determined by the biuret method, was used to study the effects of ethambutol on the cell-free synthesis of arabinosecontaining oligosaccharides.Purification of arabinogalactan from commercial source. To a solution of plant arabinogalactan (1.0 g; K and K Laboratories, Inc., Plainview, N.Y.) in 20 ml of water, 24.4 ml of ethanol was added, and the mixture was centrifuged at 500 x g for 10 min. The dark brown residue was discarded; 100 ml of ethanol was added to the supernatant, which was then mixed well and centrifuged. The resulting residue, which 1493
During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.
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