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1.  Relationship between intracellular concentration of S-adenosylhomocysteine and inhibition of vaccinia virus replication and inhibition of murine L-929 cell growth. 
9-(trans-2',trans-3'-Dihydroxycyclopent-4'-enyl)-adenine (compound 1) and -3-deazaadenine (compound 2), which are specific inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were reported earlier by our laboratory (M. Hasobe, J. G. McKee, D. R. Borcherding, and R. T. Borchardt, Antimicrob. Agents Chemother. 31:1849-1851, 1987) to have anti-vaccinia virus activity with reduced murine L-929 cell toxicity compared with the prototype compound neplanocin A. In this study, we showed that the antiviral and cytotoxic effects of compounds 1 and 2 can be related to intracellular concentrations of AdoHey, which are elevated in cells treated with these inhibitors of AdoHcy hydrolase. For example, concentrations of analogs 1 and 2 that produce 50% inhibition of vaccinia virus replication caused only slight elevations in intracellular levels of AdoHcy (from 50 [controls] to 100 to 125 [drug-treated cells] pmol/mg of protein) and elevations in the ratios of AdoHcy/S-adenosylmethionine (from 0.05 to 0.1 [controls] to 0.15 to 0.19 [drug-treated cells]). In contrast to the extreme susceptibility of virus replication to slight elevations in intracellular AdoHcy, cell viability was quite tolerant to higher levels of this metabolite. For example, concentrations of analogs 1 and 2 that produced 50% inhibition of L-929 cell replication caused significant increases in intracellular levels of AdoHcy (to 825 to 950 pmol/mg of protein) and elevations in AdoHcy/S-adenosylmethionine ratios (approximately 1.3). These data make it possible to assign a therapeutic index of 7 to 8 to these compounds on the basis of the comparison of intracellular levels of AdoHcy that caused 50% inhibition of vaccinia virus replication with those that caused 50% inhibition of L-929 cell replication.
PMCID: PMC284240  PMID: 2764532
9.  Interaction of E1040 with cephalosporinase from Citrobacter freundii GN7391. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2157-2159.
The interactions of E1040 with cephalosporinase from Citrobacter freundii, including affinity and hydrolysis, were studied in comparison with those of cefotaxime and ceftazidime. E1040 showed a higher stability at low drug concentrations and a much lower affinity for the enzyme than did cefotaxime or ceftazidime. These enzymological properties explain the high activity of E1040 against cephalosporinase-producing C. freundii.
PMCID: PMC172843  PMID: 2694954
10.  Comparative in vitro activities of pristinamycin and other antimicrobial agents against genital pathogens. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2152-2154.
The MICs of pristinamycin for genital pathogens were compared with those of ampicillin, tetracycline, erythromycin, and ciprofloxacin. Pristinamycin was active against all the strains studied. Because of this activity and its lack of toxicity, pristinamycin might be a valuable therapeutic agent for treating major sexually transmitted diseases.
PMCID: PMC172841  PMID: 2515796
11.  Tetracyclines as antiparasitic agents: lipophilic derivatives are highly active against Giardia lamblia in vitro. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2144-2145.
Comparisons of the inhibitory activities of different tetracyclines have been reported for Plasmodium falciparum but no other parasites. The in vitro response of the intestinal parasite Giardia lamblia to six tetracyclines in current use was determined. In addition, the experimental drug thiacycline (EMD 33,330) was evaluated. Three groups were discerned, with representative 50 and 90% inhibitory concentrations of, respectively, 36 and 130 (tetracycline), 6.4 and 22 (doxycycline), and 1.8 and 3.4 (thiacycline) micrograms/ml. These dramatic differences in activity correlate with increased lipophilicity.
PMCID: PMC172838  PMID: 2619281
12.  In vitro activities of cefcanel and some other cephalosporins against Pasteurella multocida. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2142-2143.
Thirty-five strains of Pasteurella multocida from humans and animals were tested for susceptibility to five cephalosporins by a broth dilution method. Cefcanel showed high activity against all isolates (MIC and MBC, less than or equal to 0.64 micrograms/ml). The corresponding figure for cefaclor and cefuroxime was 2.56 micrograms/ml. Cefadroxil and cephalexin were the least active compounds tested.
PMCID: PMC172837  PMID: 2619280
13.  In vitro susceptibility of Nocardia spp. to a new fluoroquinolone, tosufloxacin (T-3262). 
Antimicrobial Agents and Chemotherapy  1989;33(12):2140-2141.
The in vitro activity of a new fluoroquinolone, tosufloxacin (T-3262), against 111 pathogenic Nocardia strains was studied by an agar dilution method and compared with the activities of other fluoroquinolones. All strains were susceptible to tosufloxacin, and the drug was 2 to 20 times more active than four other quinolones tested. Nocardia farcinica was the Nocardia species most susceptible to tosufloxacin.
PMCID: PMC172836  PMID: 2619279
14.  Susceptibility of anaerobic bacteria to ALP 201. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2137-2139.
The activity of ALP 201 against 350 strains of anaerobic bacteria was determined by an agar dilution method. Its activity was compared with those of piperacillin, cefoxitin, imipenem, clindamycin, metronidazole, and chloramphenicol. ALP 201 and imipenem were the most active agents tested. Based on these results, ALP 201 appears to be a promising antimicrobial agent for anaerobic infections and warrants further clinical investigations.
PMCID: PMC172835  PMID: 2619278
15.  WIN 57273 is bactericidal for Legionella pneumophila grown in alveolar macrophages. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2132-2136.
The in vitro antimicrobial activity of WIN 57273, a new quinolone antimicrobial agent, was determined for 21 Legionella strains, using broth macrodilution and agar dilution testing methods; ciprofloxacin and erythromycin were tested as well. Three different buffered yeast extract media were used for the agar dilution studies, two of which were made with starch rather than charcoal. Broth macrodilution susceptibility testing was performed with buffered yeast extract broth and two Legionella pneumophila strains. Antimicrobial inhibition of L. pneumophila growth in guinea pig alveolar macrophages was also studied, using a method able to detect bacterial killing. The MICs for 90% of the 21 strains of Legionella spp. grown on buffered charcoal yeast extract medium were 0.125 microgram/ml for WIN 57273, 0.25 microgram/ml for ciprofloxacin, and 1.0 micrograms/ml for erythromycin. These MICs were falsely high, because of inhibition of drug activity by the medium used. Use of less drug-antagonistic, starch-containing media did not support good growth of the test strains. The broth macrodilution MICs for two strains of L. pneumophila serogroup 1 were less than or equal to 0.03 microgram/ml for WIN 57273 and ciprofloxacin and 0.125 microgram/ml for erythromycin. WIN 57273, ciprofloxacin, and erythromycin all inhibited growth of L. pneumophila in guinea pig alveolar macrophages at concentrations of 1 microgram/ml, but only WIN 57273 prevented regrowth or killed L. pneumophila after removal of extracellular antimicrobial agent.
PMCID: PMC172834  PMID: 2619277
16.  In vitro and in vivo activities of piritetrate (M-732), a new antidermatophytic thiocarbamate. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2118-2125.
Piritetrate (M-732), a new topical antifungal agent belonging chemically to the thiocarbamates, was demonstrated to possess a potent selective antidermatophytic activity. In terms of its MICs in susceptibility testing, mainly done by using Sabouraud dextrose agar plates, piritetrate exhibited several- to 10-fold-stronger antidermatophytic activity than tolnaftate, a reference thiocarbamate. Furthermore, piritetrate was found to show a broader antifungal spectrum than tolnaftate; relatively many species and strains of dematiaceous fungi, dimorphic fungi, and some other filamentous fungi as well as a few strains of Cryptococcus neoformans were fairly susceptible to piritetrate, while almost all the tested species and strains were resistant to tolnaftate. All the tested species of the genus Candida were, however, resistant to both compounds. Variables which can influence antimicrobial activity caused few changes in the MICs of either compound against Trichophyton mentagrophytes; however, an increase in the inoculum size resulted in a significant increase in the MICs. The antidermatophytic activities of piritetrate and tolnaftate were fungistatic but not fungicidal. Piritetrate also exhibited a more potent in vitro anti-T. mentagrophytes activity than clotrimazole or tolciclate. Piritetrate and tolnaftate had no antibacterial activity. The in vivo activity of topically administered piritetrate against experimental dermal infection of guinea pigs with T. mentagrophytes was more effective than that of tolnaftate both mycologically and clinically. Piritetrate manifested no acute toxicity in laboratory animals when administered even in large quantities by the oral, intraperitoneal, and topical routes.
PMCID: PMC172832  PMID: 2619275
17.  Reactivation of peptidoglycan synthesis in ether-permeabilized Escherichia coli after inhibition by beta-lactam antibiotics. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2101-2108.
The recovery of peptidoglycan-synthesizing activity after inhibition by beta-lactam antibiotics was investigated in ether-permeabilized cells of Escherichia coli B. Such cells synthesize sodium dodecyl sulfate-insoluble peptidoglycan when provided with UDP-linked precursors and Mg2+. The ability of beta-lactam antibiotics to inhibit the synthesis of peptidoglycan was correlated with their affinity for penicillin-binding proteins 1A and 1Bs. Penicillin-binding protein 1Bs is thought to be the major peptidoglycan synthetase in E. coli and is a major lethal target for beta-lactam antibiotics. Ether-treated bacteria were preincubated with concentrations of beta-lactams sufficient to completely inhibit peptidoglycan synthesis and then treated with beta-lactamases to inactivate free antibiotic prior to measurement of peptidoglycan synthesis. At 40 min after beta-lactamase treatment, the rate of peptidoglycan synthesis was about 74% of the control rate in cells pretreated with ampicillin, but only 15% of the control in cells pretreated with penicillin G or azlocillin. Reversal of inhibition by several other antibiotics fell between these extremes. When cross-linking of peptidoglycan was measured specifically, reversal of inhibition by ampicillin also occurred more readily than that by penicillin G. Reactivation of peptidoglycan synthesis was not due to de novo synthesis of penicillin-binding proteins since it occurred under conditions that did not allow incorporation of [14C]leucine. We conclude that there is considerable variation in the stability of the inactive acyl enzymes formed between various beta-lactams and penicillin-binding protein 1Bs, with those formed by penicillin G being relatively long-lived.
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PMCID: PMC172829  PMID: 2515794
18.  Microbial glycosylation of erythromycin A. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2089-2091.
Erythromycin A (compound 1) was inactivated by Streptomyces vendargensis ATCC 25507 in fermentation. The inactivation product was isolated and characterized by nuclear magnetic resonance and mass spectroscopy as 2'-(O-[beta-D-glucopyranosyl])erythromycin A (compound 2). The MICs of compounds 1 and 2 were determined. Compound 2 lacked antibiotic activity when tested against several gram-positive pathogens, as well as S. vendargensis.
PMCID: PMC172826  PMID: 2619274
19.  Binding and killing of bacteria by bismuth subsalicylate. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2075-2082.
Bismuth subsalicylate (BSS) is a compound without significant aqueous solubility that is widely used for the treatment of gastrointestinal disorders. BSS was able to bind bacteria of diverse species, and these bound bacteria were subsequently killed. A 4-log10 reduction of viable bacteria occurred within 4 h after a 10 mM aqueous suspension of BSS was inoculated with 2 x 10(6) Escherichia coli cells per ml. Binding and killing were dependent on the levels of inoculated bacteria, and significant binding but little killing of the exposed bacteria occurred at an inoculum level of 2 x 10(9) E. coli per ml. Intracellular ATP decreased rapidly after exposure of E. coli to 10 mM BSS and, after 30 min, was only 1% of the original level. Extracellular ATP increased after exposure to BSS, but the accumulation of extracellular ATP was not sufficient to account for the loss of intracellular ATP. The killing of bacteria exposed to BSS may have been due to cessation of ATP synthesis or a loss of membrane integrity. Bactericidal activity of BSS was also investigated in a simulated gastric juice at pH 3. Killing of E. coli at this pH was much more rapid than at pH 7 and was apparently due to salicylate released by the conversion of BSS to bismuth oxychloride. It is proposed that the binding and killing observed for BSS contribute to the efficacy of this compound against gastrointestinal infections such as traveler's diarrhea.
PMCID: PMC172824  PMID: 2694949
20.  In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2069-2074.
WIN 54954 (5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl]-3- methylisoxazole) is a new member of the class of broad-spectrum antipicornavirus compounds known to bind in a hydrophobic pocket within virion capsid protein VP1. In plaque reduction assays, WIN 54954 reduced plaque formation of 50 of 52 rhinovirus serotypes (MICs ranged from 0.007 to 2.2 micrograms/ml). A concentration of 0.28 microgram/ml was effective in inhibiting 80% of the 52 serotypes tested (EC80). WIN 54954 was also effective in inhibiting 15 commonly isolated enteroviruses, with an EC80 of 0.06 microgram/ml. Furthermore, WIN 54954 was effective in reducing the yield of two selected enteroviruses in cell culture by 90% at concentrations approximately equal to their MICs. The therapeutic efficacy of intragastrically administered WIN 54954 was assessed in suckling mice infected with coxsackievirus A-9 or echovirus type 9 (Barty) 2.5 days prior to initiation of therapy. Single daily doses of 2 and 100 mg/kg protected 50% of the mice from developing paralysis (PD50) following infection with coxsackievirus A-9 and echovirus-9, respectively. At the PD50 doses for these two viruses, levels of WIN 54954 in serum were maintained above the in vitro MICs for a significant portion of the dosing interval. The dose-dependent reduction in viral titers observed in coxsackievirus A-9-infected mice correlated well with the therapeutic dose response. The potency and spectrum of WIN 54954 make it a potentially useful compound for the treatment of human enterovirus and rhinovirus infections.
PMCID: PMC172823  PMID: 2559655
21.  Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2063-2068.
Saperconazole (R 66905) is a broad-spectrum antifungal triazole with potent in vitro activity against Aspergillus spp. A total of 279 strains were tested in brain heart infusion broth. Development of the Aspergillus spp. was completely inhibited at 0.1 and 1 microgram of saperconazole per ml for 80.3 and 99.6% of the strains, respectively. Normal and immunocompromised guinea pigs were infected intravenously with Aspergillus fumigatus and treated orally, intravenously, or intraperitoneally with saperconazole or intraperitoneally with amphotericin B. Leukopenia, neutropenia, lymphocytosis, and monocytosis were obtained with mechlorethamine hydrochloride; leukopenia, neutrophilia, and lymphopenia were obtained with cyclophosphamide. Saperconazole was dissolved for oral treatment in polyethylene glycol and for parenteral treatment in cyclodextrins. Amphotericin B was given parenterally as Fungizone (E.R. Squibb & Sons). Treatment was given once daily for 14 days. An early starting treatment was efficacious, but the activity of saperconazole was maintained even when the onset of the treatment was delayed to the moribund state. The activity of saperconazole was not altered in immunocompromised animals. Saperconazole was clearly superior to amphotericin B and free of side effects. The oral and parenteral formulations of saperconazole were equipotent. The systemic activity of saperconazole in guinea pigs was confirmed in invasive aspergillosis in pigeons.
PMCID: PMC172822  PMID: 2619273
22.  In vitro activities of lomefloxacin, tetracycline, penicillin, spectinomycin, and ceftriaxone against Neisseria gonorrhoeae and Chlamydia trachomatis. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2049-2051.
In vitro lomefloxacin was highly active against 208 penicillin-susceptible and -resistant isolates of Neisseria gonorrhoeae. However, its MIC and MBC against 10 isolates of Chlamydia trachomatis were 2 and greater than 4 micrograms/ml, respectively.
PMCID: PMC172820  PMID: 2533473
23.  Postinfection therapy of arbovirus infections in mice. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2126-2131.
Most antiviral agents are efficacious prophylactically in vivo, and a few are efficacious for postinfection (p.i.) therapy. To explore possibilities for p.i. therapy of encephalogenic Banzi virus (BZV) and Semliki Forest virus infections in mice, we evaluated candidate antiviral therapies after development of the first clinical signs of infection. The earliest clinical indication of BZV viremia in mice is a rise in core body temperature beginning on day 3 p.i. BZV-infected mice showing elevated core body temperatures (greater than or equal to 37.3 degrees C) on days 3 and 4 p.i. were treated intraperitoneally with the interferon inducer poly(ICLC) (80 micrograms per mouse) and/or specific antiserum. Combined therapy on day 3 of a BZV infection protected over 75% of mice showing clinical evidence of viral disease before treatment. Protection against early brain infection must occur on day 4 p.i., since by that day BZV has started multiplying in the brains of the mice. Significant protection occurred with antiserum alone and increased with poly(ICLC). Similar protection was obtained during Semliki Forest virus viremia, but this infection is so rapid that the first clinical signs are reliably detectable only after viremia.
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PMCID: PMC172833  PMID: 2619276
24.  Structural features related to hydrolytic activity against ceftazidime of plasmid-mediated SHV-type CAZ-5 beta-lactamase. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2160-2163.
Tryptic peptides of the novel ceftazidimase CAZ-5 were sequenced by manual Edman degradation and aligned according to strong homology (more than 98%) with SHV-1 and SHV-2 beta-lactamase sequences. CAZ-5 differed from SHV-1 by five amino acid substitutions. Unusually high activity of CAZ-5 towards ceftazidime was imputed to substitution of a Lys for a Glu at position 214 of the mature protein.
PMCID: PMC172844  PMID: 2694955
25.  In vitro susceptibilities of Rickettsia rickettsii and Rickettsia conorii to roxithromycin and pristinamycin. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2146-2148.
In vitro susceptibilities of Rickettsia rickettsii and Rickettsia conorii to roxithromycin, pristinamycin, and the pristinamycin compounds, P1 and P2, were determined by a dye uptake assay and a plaque assay. The MICs were 1 microgram/ml for roxithromycin, 2 micrograms/ml for pristinamycin, greater than 256 micrograms/ml for P1, and 2 micrograms/ml for P2. Compounds P1 and P2 did not share synergetic activity. The toxicity of each compound was determined by a dye uptake assay. Toxic concentrations were 128 micrograms/ml for roxithromycin, 32 micrograms/ml for pristinamycin, greater than 256 micrograms/ml for P1, and 32 micrograms/ml for P2. Roxithromycin and pristinamycin could be useful in the treatment of Rocky Mountain spotted fever and Mediterranean spotted fever.
PMCID: PMC172839  PMID: 2515795

Results 1-25 (462)