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New Antibiotic on the Horizon?

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New Antibiotic on the Horizon? RESEARCH HIGHLIGHTS the β-ketoacyl-acyl carrier protein increased the binding signal and synthase FabF. To increase the chance confirmed the authors’ hypothesis of identifying a compound that that platensimycin only binds to the selectively targets FabF, the authors acyl intermediate. engineered the Gram-positive patho- The transient nature of the gen Staphylococcus aureus to express acyl–FabF complex also made antisense RNA against FabF. This attempts to obtain a crystal structure renders the bacteria more sensitive of platensimycin bound to its target to inhibitors of this enzyme, and so challenging. However, by substituting comparison of growth inhibition of the cysteine residue in the active the wild-type strain with that of the site of the enzyme with glutamine, antisense strain enables the identi- the side chain of which is thought fication of genuine FabF-selective to mimic a bound fatty acid, the inhibitors present in the fermentation authors produced a stable FabF samples. This screen identified a variant–platensimycin complex that potent antibiotic, platensimycin, was amenable to crystallographic which could otherwise have been analysis. From this they were able overlooked in a conventional to determine that platensimycin screening assay. targets the malonate-binding site Platensimycin was found to have of FabF, thereby blocking fatty acid broad-spectrum activity against biosynthesis, and that the formation Gram-positive bacteria in in vitro of the acyl–FabF intermediate opens ANTIBACTERIAL DRUGS assays and was able to eradicate up the active site of FabF, a confor- systemic S. aureus infection in mice. mational change that is essential for Importantly, platensimycin shows platensimycin binding. New antibiotic no cross-resistance with other In recent decades, there has been classes of antibiotics, and is active a dearth of new classes of antibiotic. against bacterial infections that are Platensimycin is currently the most on the horizon? resistant to commercially available potent inhibitor of FabF, as well drugs, such as methicillin-resistant as being the only inhibitor of this S. aureus and vancomycin-resistant enzyme that has broad-spectrum A return to investigating natural enterococci. activity. Fatty acid biosynthesis is so products as a source of antimicrobials To verify that the mode of action far an under-targeted pathway, and so could hold the key to tackling multi- of platensimycin was the selective it has considerable potential for drug drug resistant bacteria. Writing in Platensimycin targeting of FabF, the authors used a development. On the basis of these Nature, Wang and colleagues describe radioactive platensimycin derivative. data, and with structural information the isolation and characterization of looks to be Initially, the binding affinities of in hand, platensimycin looks to be a platensimycin, a small molecule that a promising the derivative for FabF were much promising first step towards a new represents a new class of anti biotic first step lower than anticipated, which led first-in-class antibacterial drug. and which has broad, potent activity towards a new the authors to propose that platensi- Samantha Barton against Gram-positive pathogens. mycin was targeting the transiently first-in-class A pathway yet to be fully formed (and so difficult to detect) ORIGINAL RESEARCH PAPER Wang, J. et al. exploited for antibiotic drug discov- antibacterial acyl–FabF intermediate. Indeed, Platensimycin is a selective FabF inhibitor with ery is fatty acid biosynthesis. A key preparation of a stable acyl–enzyme potent antibiotic properties. Nature 441, drug. 358–361 (2006) enzyme involved in this pathway is complex to mimic the transient form RESEARCH HIGHLIGHTS ADVISORS ERIK DE CLERCQ F. PETER GUENGERICH MADS KROGSGAARD THOMSEN CHRISTOPHER LIPINSKI Katholieke Universiteit Leuven, Belgium Vanderbilt University Nashville, TN, USA Novo Nordisk, Bagsvaerd, Denmark Pfizer Global Research and Development, RODERICK FLOWER FRANZ HEFTI HUGO KUBINYI Groton, CT, USA William Harvey Research Institute, QMW, Rinat Neuroscience Corporation, Palo Alto, University of Heidelberg, Germany TOMI SAWYER London, UK CA, USA ROBERT LANGER Massachusetts Institute of Ariad Pharmaceuticals, Cambridge, MA, USA YOSHIJI FUJITA JOAN HELLER BROWN Technology Cambridge, MA, USA JANET WOODCOCK Clinical Proteome Center, Tokyo Medical University of California San Diego, JULIO LICINIO University of California Los Food & Drug Administration, Rockville, University CA, USA Angeles, CA, USA MD, USA NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | JULY 2006 | 539 RESEARCH HIGHLIGHTS LIVER DISEASE murine model of acute liver injury the phosphatidylinositol 3-kinase-Akt to demonstrate that CB1 receptors and extracellular-regulated kinase are involved in the induction of two (ERK) pathways, which are necessary A new treatment fibrogenic markers: the profibrogenic for the growth and survival of hepatic cytokine transforming growth factor myofibroblasts. Cells isolated from for liver fibrosis? (TGF)-β1 and smooth muscle α-actin. CB1 knockout mice showed decreased Administration of rimonabant reduced phosphorylation of ERK and Akt, as did Chronic liver injury in response to expression of both markers, and there rimonabant-treated wild-type hepatic alcohol or hepatitis virus B or C is was a similar reduction in fibrogenic myofibroblasts, suggesting that CB1 associated with liver fibrosis, and its This study marker expression in CB1 knockout mice, receptors on hepatic myofibroblasts may endstage, cirrhosis, is a major public opens the with or without rimonabant treatment. either be activated by an endogenous health problem. However, at present, To further assess the role of CB1 ligand or be constitutively active. there are no effective antifibrotic drugs possibility that receptors in chronic liver injury, three Overall, these results clarify the approved for human use. In a recent rimonabant mouse models were used: chronic CCl4 profibrogenic role of the CB1 receptor. paper in Nature Medicine, Teixeira-Clerc might also intoxication, chronic thioacetamide And although yet to be tested for liver and colleagues now show that use of the intoxication and bile duct ligation. fibrosis in clinical trials, this study cannabinoid CB1 receptor antagonist have potential Rimonabant lowered the fibrogenic opens the possibility that rimonabant, rimonabant could be a new therapeutic in the treat- response, independently of the agent which has been recommended to strategy for this condition. ment of liver used to induce liver injury, as shown receive marketing authorization for the The authors recently found that during by a decrease in fibrosis area, reduced treatment of obesity by the European the course of chronic hepatitis C, daily fibrosis. hepatic expression of TGF-β1, and Medicines Agency, might also have cannabis use is an independent predictor decreased number of liver fibrogenic potential in the treatment of liver fibrosis. of fibrosis progression. They therefore cells. Similar reduction of fibrogenesis Charlotte Harrison sought to determine if CB1 receptors was observed in CB1 knock-out mice. might be involved in liver fibrosis. The authors then focused on how ORIGINAL RESEARCH PAPER Teixeira-Clerc, T. Firstly, using immuno-blotting and antagonism of CB1 receptors might et al. CB1 cannabinoid receptor antagonism: a immunohistocytochemistry, Teixeira- reduce the accumulation of hepatic new strategy for the treatment of liver fibrosis. Nature Med. 12, 671–676 (2006) Clerc et al. showed that CB1 receptor myofibroblasts. Hepatic myofibroblasts FURTHER READING Lotersztajn, S. et al. Hepatic expression was upregulated in human from CB1 receptor knockout mice fibrosis: molecular mechanisms and drug targets. cirrhotic liver samples, predominantly in displayed increased apoptosis, whilst Annu. Rev. Pharmacol. Toxicol 45, 605–628 (2005) | hepatic myofibro blasts, the fibrogenic Kunos, G. et al. Cannabinoids hurt, heal in rimonabant was able to inhibit their cirrhosis. Nature Med. 12, 608–609 (2006) cells of the liver. They then used a proliferation. They also investigated NEUROLOGICAL DISORDERS Homing in on the target of antidepressants The mechanism of action of Neurons are continuously gener- expression of typical marker proteins most commonly used ated in the dentate gyrus region such as nestin, combined with antidepressants is of the hippocampus throughout dense packing of the cells within the poorly defined life. In animal models, this activity dentate gyrus. The authors therefore and a better increases in response to various types generated mice in which a fluorescent understanding of anti depressant therapy, including signal was localized specifically to of the effects of selective serotonin reuptake inhibitors the nucleus of these cells, producing these drugs on (SSRIs) such as fluoxetine, and poten- a labelling pattern that was easier to the brain could tially contributes to their therapeutic quantify. In combination with staining lead to new thera- effects. However, the precise stage of for various proteins that are expressed peutic approaches. the multi-step process of neurogen- at different stages of neurogenesis, the A potential link between esis at which SSRIs actually intervene authors defined six distinct sequential neurogenesis and antidepressant is unknown. A clearer understanding stages of neuronal development and treatment announced several years of the progenitor cell type targeted investigated the effects of chronic ago generated excitement in the field,
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