Alistair Brown

Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.

Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis.

The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.

Shigatoxin encoding Bacteriophage ϕ24B modulates bacterial metabolism to raise antimicrobial tolerance.

How temperate bacteriophages play a role in microbial infection and disease progression is not fully understood. They do this in part by carrying genes that promote positive evolutionary selection for the lysogen. Using Biolog phenotype microarrays and comparative metabolite profiling we demonstrate the impact of the well-characterised Shiga toxin-prophage ϕ24B on its Escherichia coli host MC1061. As a lysogen, the prophage alters the bacterial physiology by increasing the rates of respiration and cell proliferation. This is the first reported study detailing phage-mediated control of the E. coli biotin and fatty acid synthesis that is rate limiting to cell growth. Through ϕ24B conversion the lysogen also gains increased antimicrobial tolerance to chloroxylenol and 8-hydroxyquinoline. Distinct metabolite profiles discriminate between MC1061 and the ϕ24B lysogen in standard culture, and when treated with 2 antimicrobials. This is also the first reported use of metabolite profiling to characterise the physiological impact of lysogeny under antimicrobial pressure. We propose that temperate phages do not need to carry antimicrobial resistance genes to play a significant role in tolerance to antimicrobials.

Communication Technology and Narrative: Letters, Instant Messaging, and Mobile Phones in Three Romantic Novels

Subscriptions Direct all orders to Duke University Press, Journals Customer Relations 905 W. Main St., Suite 18B, Durham, NC 27701. Annual subscription rates: print-plus-electronic institutions,

Is posthuman incest possible

426; print-only institutions,

Bacteriophage ɸ24B modulates microbial physiology and antimicrobial tolerance by hijacking the fatty acid synthesis pathway

400; e-only institutions,

Stx-phage vB_EcoP 24B sculpting host bacterial function

338; individuals,

Are Video Game Narratives Postmodern

40; students,

Proving dissemination is only one half of your impact story: Twitter provides proof of real-time engagement with the public

20. For information on subscriptions to the e-Duke Journals Scholarly Collections, contact libraryrelations@dukeupress.edu. Print subscriptions: add

Ulysses as an RPG

14 postage and applicable HST (including 5% GST) for Canada; add