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Biomedical subjects

J F Barrett

Publications and source records attributed to J F Barrett.

At least 55 records · Page 3Linked to original sources
PubMed1999

Comparison of efficacies of oral levofloxacin and oral ciprofloxacin in a rabbit model of a staphylococcal abscess.

Oral levofloxacin was compared to oral ciprofloxacin in a Staphylococcus aureus subcutaneous abscess model in rabbits. Rabbits were surgically prepared with subcutaneous wiffle balls (43 mm in diameter) and allowed to recover for 4 to 6 weeks. Rabbits were infected by direct injection into the capsule with S. aureus ATCC 29213 (5 x 10(5) CFU) and were allowed to remain infected for 8 days before the initiation of anti-infective treatment. Efficacy was determined by assessing the bacterial load within the capsule over a 10-day treatment period. In single-dose pharmacokinetic studies in infected rabbits, similar area under the concentration-time curve/MIC ratios were obtained in the plasma and abscess fluid for levofloxacin at 45 mg/kg of body weight and ciprofloxacin at 200 mg/kg of body weight. Similar efficacies were seen with levofloxacin at 45 mg/kg/day and ciprofloxacin 400 mg/kg/day by day 10. In this model, levofloxacin was significantly more efficacious than ciprofloxacin (P < 0.01).

Abscess↗
PubMed1999

39th Interscience Conference on Antimicrobial Agents and Chemotherapy of the American Society for Microbiology.

The 39th ASM ICAAC Meeting, attended by over 16,000 delegates, highlighted numerous late-stage development antibacterials. The presentation of over 600 reports (posters, symposia and oral presentations) regarding resistance emergence underscores the evolving landscape of antibiotic susceptibility worldwide. Although bacterial genomic efforts are slowly expanding the potential sources of novel targets, the established antibacterial classes, including quinolones, beta-lactams, protein synthesis inhibitors and carbapenems, were most prevalent among the presentations. Quinolones dominated this conference, with many presentations of moxifloxacin (> 72 presentations), gatifloxacin (> 66 presentations) and gemifloxacin (> 59 presentations). The new class of antibacterials, the oxazolidinones, represented by Linezolid, was also highlighted.

Journal Article↗
PubMed1999

Quinolone update.

Explore the source record for details and available documents.

Journal Article↗
PubMed1998

Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria.

A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 &microM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).

Anti-Bacterial Agents↗
PubMed1998

SAR studies of diaryltriazoles against bacterial two-component regulatory systems and their antibacterial activities.

A series of diaryltriazole analogs was discovered to inhibit bacterial two-component regulatory systems in our primary assays, KinA/Spo0F and NRII/NRI. They also showed inhibitory activity in whole cell mechanism-based assays, and they possessed potent activities against several strains of Gram-positive pathogenic bacteria in the standard MIC broth assay.

Anti-Bacterial Agents↗
PubMed1998

Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel.

This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.

Anti-Bacterial Agents↗
PubMed1998

Antibacterial agents that inhibit two-component signal transduction systems.

A class of antibacterials has been discovered that inhibits the growth of Gram-positive pathogenic bacteria. RWJ-49815, a representative of a family of hydrophobic tyramines, in addition to being a potent bactericidal Gram-positive antibacterial, inhibits the autophosphorylation of kinase A of the KinA::Spo0F two-component signal transduction system in vitro. Analogs of RWJ-49815 vary greatly in their ability to inhibit growth of bacteria and this ability correlates directly with their activity as kinase A inhibitors. Compared with the potent quinolone, ciprofloxacin, RWJ-49815 exhibits reduced resistance emergence in a laboratory passage experiment. Inhibition of the histidine protein kinase::response regulator two-component signal transduction pathways may present an opportunity to depress chromosomal resistance emergence by targeting multiple proteins with a single inhibitor in a single bacterium. Such inhibitors may represent a class of antibacterials that potentially may represent a breakthrough in antibacterial therapy.

Anti-Bacterial Agents↗
PubMed1998

DNA gyrase inhibitory activity of ellagic acid derivatives.

Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.

Ellagic Acid↗
PubMed1998

38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 24-27, 1998, San Diego, CA, USA.

This year's ICAAC meeting was dominated by exciting late-stage development antibiotics that represent breakthroughs in covering pathogens of unmet medical need, including drug-resistant pathogens. There are several exciting antibiotics in late-stage development, among them, linezolid, gatifloxacin, moxifloxacin, SB-265805, HMR 3647, SCH27899 and the resurrected daptomycin. The development of new technology for screening and the cross-application into genomics have led to numerous breakthroughs in techniques and strategies for the identification of novel prokaryotic targets.

Journal Article↗
PubMed1998

Importance of antifungal drug-resistance: clinical significance and need for novel therapy.

The incidence of fungal infections has increased dramatically over the past few decades due to the increase in the members of the population susceptible to such infections. This population includes individuals undergoing chemotherapy for cancer, those enduring long-term treatment with antibacterial agents, those receiving immunosuppressive drugs following transplantations, or those immunosuppressed due to diseases, such as AIDS, or malignancies. Newer antifungal agents, namely the triazoles, have aided in both the treatment of fungal infections and in the prevention of disease in susceptible individuals. However, resistance to the azoles, as well as to the polyenes, has resulted in clinical failures. Only a few potential antifungal targets have been exploited to date and there is a critical need for the discovery and development of novel antifungal agents that will result in improved therapy in this ever-expanding patient population. An increased intensity in the study of fungal pathogens at the molecular level holds the key to such advances.

Journal Article↗
PubMed1998

Efflux pumps in bacteria: overview, clinical relevance, and potential pharmaceutical target.

Trends in microbial resistance suggest a dramatic increase in the frequency of reports of multi-drug efflux pumps in bacteria and fungi. Although it is difficult to determine whether this increase is due to the increased attention given to this resistance mechanism, or an increase in frequency, efflux pumps are becoming an important consideration in resistance emergence. These efflux pumps comprise at least four different classes in Gram-positive and Gram-negative bacteria, as well as in Streptomyces and fungi. As more efflux pumps are characterised and studied, both biochemically and structurally, the opportunity for intervention may arise.

Journal Article↗
PubMed1998

Why are there no new antibiotics?

Renewed efforts are underway in the pharmaceutical industry to address the growing problem of antibiotic resistant pathogens. With this rededication to novel antibiotic discovery, new tools and technologies are being deployed to understand critical therapeutic intervention points in bacterial metabolism.

Editorial↗
PubMed1998

98th General Meeting of the American Society for Microbiology. May 17-21, 1998; Atlanta, GA.

The 98th General Meeting of the American Society for Microbiology was held from May 17-21, 1998, in Atlanta, Georgia and was attended by well over 10,000 scientists. The theme of antibiotic resistance dominated the meeting with numerous presentations on resistance mechanisms, new targets and potential antimicrobial agents. Many new insights into the understanding of microbial physiology were provided. Microbial genomics was shown to be revolutionizing the way in which scientists can probe and explore bacteria and fungi.

Journal Article↗
PubMed1997

Protein structure determination using a combination of comparative modeling and NMR spectroscopy. Application to the response regulator protein, Spo0F.

A practical combination of comparative modeling and NMR spectroscopy was used to generate a three-dimensional structure of the response regulator protein, Spo0F. The backbone structure obtained compares to the Spo0F Y13S mutant X-ray structure with an rmsd of 2.0 A. We provide results which suggest that structures obtained by this method are suitable for drug discovery. The results of the GRID and DOCK methods as applied to the model and X-ray structures of Spo0F are remarkably similar and tend to suggest the same design conclusions. This trend is illustrated by these same techniques applied to two experimentally derived structures of the analogous protein, CheY, which exhibit a pairwise rmsdBB on the same order as that found for the two Spo0F structures.

Amino Acid Sequence↗