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Cambridge, MA, United States

Trzasko A.,Novartis | Leeds J.A.,Novartis | Praestgaard J.,Translational Sciences, Inc. | LaMarche M.J.,Global Discovery Chemistry | McKenney D.,Novartis
Antimicrobial Agents and Chemotherapy | Year: 2012

LFF571 is a novel semisynthetic thiopeptide antibiotic with potent activity against a variety of Gram-positive pathogens, including Clostridium difficile. In vivo efficacy of LFF571 was compared to vancomycin in a hamster model of C. difficile infection (CDI). Infection was induced in Golden Syrian hamsters using a toxigenic strain of C. difficile. Treatment started 24 h postinfection and consisted of saline, vancomycin, or LFF571. Cox regression was used to analyze survival data from a cohort of animals evaluated across seven serial experimental groups treated with vancomycin at 20 mg/kg, LFF571 at 5 mg/kg, or vehicle alone. Survival was right censored; animals were not observed beyond day 21. At death or end of study, cecal contents were tested for C. difficile toxins A and B. In summary, the data showed that 5 mg/kg LFF571 decreased the risk of death by 79% (P < 0.0001) and 69% (P = 0.0022) compared with saline and 20 mg/kg vancomycin, respectively. Further analysis of the pooled data indicated that the survival benefit of LFF571 treatment at 5 mg/kg compared to vancomycin at 20 mg/kg was due primarily to a decrease in the risk of recurrence after end of treatment. Animals successfully treated with LFF571 or vancomycin had no detectable C. difficile toxin. Overall, LFF571 was more efficacious at the end of the study, at a lower dose, and with fewer recurrences, than vancomycin in the hamster model of CDI. LFF571 is being assessed in humans for safety and efficacy in the treatment of C. difficile infections. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source


Leeds J.A.,Novartis | Sachdeva M.,Novartis | Mullin S.,Novartis | Dzink-Fox J.,Novartis | LaMarche M.J.,Global Discovery Chemistry
Antimicrobial Agents and Chemotherapy | Year: 2012

LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10-11 to 1.2 × 10-9. Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source


Leeds J.A.,Novartis | LaMarche M.J.,Global Discovery Chemistry | Brewer J.T.,Global Discovery Chemistry | Bushell S.M.,Global Discovery Chemistry | And 26 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC 90 ≤ 0.25 μg/ml) but weaker against the streptococci (MIC 90 ≥ 4 μg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED 50) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED 50 of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source


Kwak Y.,Global Discovery Chemistry | Coppola G.,Global Discovery Chemistry | Forster C.J.,Global Discovery Chemistry | Gilmore T.A.,Global Discovery Chemistry | And 14 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

A series of 2-[(2,6)-dimethylphenyl]benzimidazole analogs displayed strong potential for mutagenicity following metabolic activation in either TA98 or TA100 Salmonella typhimurium strains. The number of revertants was significantly reduced by replacing the 2,6-dimethylphenyl group with a 2,6-dichlorophenyl moiety. Time-dependent CYP3A4 inhibition was also observed with a compound containing a 2-[(2,6)-dimethylphenyl] benzimidazole ring, implying risk for this scaffold to generate reactive metabolites. © 2011 Published by Elsevier Ltd. Source


Lamarche M.J.,Global Discovery Chemistry | Leeds J.A.,Novartis | Dzink-Fox J.,Novartis | Gunderson K.,Global Discovery Chemistry | And 7 more authors.
Journal of Medicinal Chemistry | Year: 2011

4-Aminothiazolyl analogues of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for Gram positive bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability, and its decomposition revealed a novel, structurally simplified, des-thiazole analogue of 1. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined. © 2011 American Chemical Society. Source

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