In vitro activities of linezolid, meropenem, and quinupristin-dalfopristin against group C and G streptococci, including vancomycin-tolerant isolates.

The in vitro activities of meropenem, linezolid, quinupristin-dalfopristin, vancomycin, and penicillin against 130 clinical isolates of group C and G streptococci, including vancomycin-tolerant isolates, were evaluated. Meropenem, linezolid, quinupristin-dalfopristin, vancomycin, and penicillin MICs at which 90% of the isolates were inhibited were 0.06, 2.0, 0.25, 0.5, and < or = 0.016 microg/ml, respectively. Meropenem, linezolid, quinupristin-dalfopristin, and penicillin were active against group C and G streptococci, including vancomycin-resistant strains.

1,7-Asymmetric induction in a nitrogen ring expansion process facilitated by in situ tethering.

[formula: see text] There are only a few methods for the asymmetric ring expansion of prochiral ketones. Symmetrically substituted cyclohexanones can be converted to the corresponding ring-expanded caprolactam with excellent 1,7-diastereoselectivity (> or = 93% ds) and yields (> or = 86%), using a chiral hydroxy azide-mediated Schmidt reaction.

Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication.

Human rhinovirus, the chief cause of the common cold, contains a positive-sense strand of RNA which is translated into a large polyprotein in infected cells. Cleavage of the latter to produce the mature viral proteins required for replication is catalyzed in large part by a virally encoded cysteine proteinase (3Cpro) which is highly selective for -Q approximately GP- cleavage sites. We synthesized peptidyl derivatives of vinylogous glutamine or methionine sulfone esters (e.g., Boc-Val-Leu-Phe-vGln-OR: R = Me, 1; R = Et, 2) and evaluated them as inhibitors of HRV-14 3C protease (3Cpro). Compounds 1 and 2 and several related tetra- and pentapeptide analogues rapidly inactivated 3Cpro with submicromolar IC50 values. Electrospray mass spectrometry confirmed the expected 1:1 stoichiometry of 3Cpro inactivation by 1, 2, and several other analogues. Compound 2 also proved to be useful for active site titration of 3Cpro, which has not been possible heretofore because of the lack of a suitable reagent. In contrast to 1, 2, and congeners, peptidyl Michael acceptors lacking a P4 residue have greatly reduced or negligible activity against 3Cpro, consistent with previously established structure-activity relationships for 3Cpro substrates. Hydrolysis of the P1 vinylogous glutamine ester to a carboxylic acid also decreased inhibitory activity considerably, consistent with the decreased reactivity of acrylic acids vs acrylic esters as Michael acceptors. Incorporating a vinylogous methionine sulfone ester in place of the corresponding glutamine derivative in 1 also reduced activity substantially. Compounds 1 and 2 and several of their analogues inhibited HRV replication in cell culture by 50% at low micromolar concentrations while showing little or no evidence of cytotoxicity at 10-fold higher concentrations. Peptidyl Michael acceptors and their analogues may prove useful as therapeutic agents for pathologies involving cysteine proteinase enzymes.

In vitro activity of LY333328, an investigational glycopeptide antibiotic, against enterococci and staphylococci.

The in vitro activities of LY333328 were compared with those of vancomycin, teicoplanin, and quinupristin-dalfopristin (Synercid) against 219 strains of enterococci and staphylococci, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MICs and MBCs were determined by a microtiter dilution protocol. LY333328 demonstrated superior activity against vancomycin-resistant enterococci and was the only antibiotic which was bactericidal. Its potency was comparable or superior to those of other antibiotics tested against methicillin-resistant staphylococci.

Evaluation of interpretive criteria of agar dilution and disk diffusion susceptibility tests for Neisseria gonorrhoeae.

Using strains of Neisseria gonorrhoeae from Western New York, the National Committee for Clinical Laboratory Standards' (NCCLS) interpretive criteria for disk diffusion susceptibility testing was evaluated on chocolate-Mueller-Hinton agar (CMH) and GC agar. The reference method for comparison was the NCCLS agar dilution minimum inhibitory concentration (MIC) method. Even though the zone sizes were significantly smaller on the CMH agar, the interpretations were not significantly different on either GC or CMH agars except for tetracycline. On the CMH agar, the number of tetracycline-resistant strains was greater than on GC agar: 3% of the strains failed to grow on CMH agar and 4% did not produce interpretable zone sizes for ceftriaxone. Therefore, the use of CMH is not recommended. There was a significant difference between the interpretative criteria of the MIC and the disk diffusion method only for tetracycline. Therefore, the NCCLS zone-diameter interpretation criteria for tetracycline does not seem applicable for N. gonorrhoeae isolates in the Buffalo, New York, area.

Stability of noxythiolin solutions stored in plastic and glass containers.

The stability of two different concentrations (1% and 2.5% w/v) of noxythiolin (Noxyflex and Noxyflex S) stored at a variety of temperatures (4, 20 and 37 degrees C) in both plastic and glass bottles has been examined over a period of 40 days. During this period noxythiolin solutions held at 20 degrees and 37 degrees C attained equilibrium (K = 0.285 +/- 0.015 mol/l). Neither noxythiolin nor its degradation products (N-methylthiourea and formaldehyde) were absorbed by the plastic (polypropylene) containers used. Therefore, noxythiolin solutions can be stored in certain plastic (polypropylene) containers under the same conditions as recommended for glass bottles.