(Fig. 1)For the in vitro tests, stock solutions were prepared by dissolving the compounds in water, except for ampicillin, which was dissolved in 0.1 M phosphate buffer (pH 8); DuP 721, chloramphenicol, and erythromycin, which were dissolved in dimethyl sulfoxide; ciprofloxacin, which was dissolved in 0.1 N NaOH solution; and griseofulvin, which was
The synthesis and structure/activity studies of the effect of varying the "B" group in a series of oxazolidinone antibacterials (I) are described. Two synthetic routes were used: (1) alkylation of aniline with glycidol followed by dialkyl carbonate heterocyclization to afford I (A = H, B = OH), whose arene ring was further elaborated by using electrophilic aromatic substitution methodology; (2) cycloaddition of substituted aryl isocyanates with epoxides to give A and B with a variety of values. I with B = OH or Br were converted to other "B" functionalities by using SN2 methodology. Antibacterial evaluation of compounds I with A = acetyl, isopropyl, methylthio, methylsulfinyl, methylsulfonyl, and sulfonamido and a variety of different "B" groups against Staphylococcus aureus and Enterococcus faecalis concluded that the compounds with B = aminoacyl, and particularly acetamido, were the most active of those examined in each A series, possessing MICs in the range of 0.5-4 micrograms/mL for the most active compounds described.
An antimicrobial system in polymorphonuclear neutrophils (PMN) consisting of myeloperoxidase and hydrogen peroxide has been proposed. This system appears to be activated during phagocytosis as a result of the stimulated metabolic activities. A lysed-granules (LG) fraction was prepared from guinea pig exudative PMN. LG alone possessed bactericidal activity which was related to the pH of the reaction; the lower the pH, the more marked the activity. When low concentrations of both H202 and LG were combined under conditions where neither factor alone exhibited significant killing power, there was a striking increase in bactericidal activity. This enhanced activity was much greater than an additive effect. The LG-peroxide antibacterial system was most active over a pH range of 4.0 to 6.0. The activity of the LG-peroxide system was essentially abolished by peroxidase inhibitors, NaN3, KCN, and aminotriazole. The antibacterial activity of this system was nonspecific in nature, being equally effective against gram-negative and gram-positive organisms.
Reproducible experimental surgical-wound infections in mice for use in the evaluation of topical antibacterial agents are described. The experimental wound was created on the backs of mice by means of a midline incision and was infected by means of cotton sutures monocontaminated with Staphylococcus aureus or Pseudomonas aeruginosa. The course of these wound infections was followed by quantitation of surface bacteria through use of a surface rinse technique. Surface wound counts of the infecting organisms thus obtained appeared to reflect the dynamics of the total wound count, as determined by homogenization of biopsied tissue. Treatment of infected wounds with a placebo cream had only a slight effect on surface wound counts and on mortality in the case of the S. aureus infection but enhanced markedly the lethality of the P. aeruginosa infection.The search for new drugs effective as topical antibacterial agents requires the careful and systematic evaluation of drugs not only in vitro but also in vivo, i.e., in the control and management of experimental infections. Several model infections for evaluating topical antibacterial agents have been developed in laboratory animals (5-7, 9, 18, 19, 21) and in humans (3,14,15,20). Although many of the models have proved to be effective in assessing topical agents, most of them do not lend themselves easily to a mass screening of potential agents. This paper describes and characterizes a relatively simple surgical-wound model in mice in which potential topical antibacterial drugs can be evaluated easily and expeditiously against Staphylococcus aureus and Pseudomonas aeruginosa wound infections.MATERIALS AND METHODS Animals. Female CF-1 mice, 18 to 20 g, purchased from a commercial source (Carworth Farms, New City, N.Y.) were used in all experiments. Mice were maintained, 10 to a cage, on wire, in temperatureand humidity-controlled quarters and were allowed food and water ad libitum.Test organisms. S. aureus SC 2406 (phage type 53/77/84/85) and P. aeruginosa SC 8822, clinical isolates from the departmental culture collection, were used as test organisms. The two organisms were maintained on brain heart infusion (BHI) agar (BBL) slants stored at 4 C, with transfers to fresh slants made monthly. For each experiment, a fresh slant was inoculated from the appropriate stock culture and incubated at 37 C for 18 h. After incubation, the growth was removed from the slant by washing with 0.1 M phosphate buffer, pH 7.2, and the resulting suspension was adjusted to a concentration of 2.0 x 109 cells/ml by use of a Klett-Summerson colorimeter with a 540-nm filter and a previously prepared standard curve. The suspension was then appropriately diluted and used for the contamination of sutures or the direct seeding of the experimental wounds. Preparation of contaminated sutures. Commercial cotton thread (Coats and Clark's, mercerized, size 8) monocontaminated with S. aureus or P. aeruginosa was used as the suture material to initiate and potentiate the experimental infection. The thread ...
The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxazolidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. [formula: see text] 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4- and 2,5-disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,5-Disubstituted and 3,4,5- and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity.
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