Predictors of long-term shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. Clinical article

The purpose of this study was to identify predictors of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (SAH). The authors evaluated the incidence of shunt-dependent hydrocephalus in a consecutive cohort of 580 patients with SAH who were admitted to the Neurological Intensive Care Unit of Columbia University Medical Center between July 1996 and September 2002. Patient demographics, 24-hour admission variables, initial CT scan characteristics, daily transcranial Doppler variables, and development of in-hospital complications were analyzed. Odds ratios and 95% CIs for candidate predictors were calculated using multivariate nominal logistic regression. Admission glucose of at least 126 mg/dl (adjusted OR 1.6; 95% CI 1.0-2.6), admission brain CT scan with a bicaudate index of at least 0.20 (adjusted OR 1.43; 95% CI 1.0-2.0), Fisher Grade 4 (adjusted OR 2.71; 95% CI 1.2-5.7), fourth ventricle hemorrhage (adjusted OR 1.78; 95% CI 1.1-2.7), and development of nosocomial meningitis (adjusted OR 2.2; 95% CI 1.4-3.7) were independently associated with shunt dependency. These data suggest that permanent CSF diversion after aneurysmal SAH may be independently predicted by hyperglycemia at admission, findings on the admission CT scan (Fisher Grade 4, fourth ventricle intraventricular hemorrhage, and bicaudate index ≥ 0.20), and development of nosocomial meningitis. Future research is needed to assess if tight glycemic control, reduction of fourth ventricle clot burden, and prevention of nosocomial meningitis may reduce the need for permanent CSF diversion after aneurysmal SAH

DISCOVERY OF LFF571 AS AN INVESTIGATIONAL AGENT FOR Clostridium difficile INFECTION

Clostridium difficile is a Gram positive, spore-forming, anaerobic bacterium which infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. The prevalence and severity of C. difficile infection are increasing, causing increased morbidity and mortality. 4-Aminothiazolyl analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of serious Gram positive bacterial infections, including C. difficile infection. Optimization of the 4-aminothiazolyl-natural product template focused on improving aqueous solubility over the natural product and previous development candidates (2, 3), and improving in vitro and in vivo antibacterial activity. Structure-activity relationships, structure-solubility relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies culminated in the identification of a dicarboxylic acid chemical series, which enhanced the solubility/efficacy profile by several orders of magnitude as compared to previous monoacid-based development candidates and led to the selection of LFF571 (4) as an investigational new drug for the treatment of C. difficile infection

The natural product argyrin B inhibits bacteria and eukaryotic cell growth by inhibition of elongation factor G1.

Argyrins are cyclic octapeptides that have antibacterial, immunosuppressive and antitumor activity. Using bacterial mutant selection and whole genome sequencing, we identified elongation factor G (EF-G) as the cellular target of argyrin B. Purified EF-G bound argyrin tightly, and the co-crystal structure of EF-G in complex with argyrin B revealed a novel binding pocket that was clearly delineated by the locations of resistance determining amino acid subtitutions. In eukaryotic cells, argyrin B was found to inhibit mitochondrial elongation factor G1 (a close homologue of EF-G), thereby blocking mitochondrial translation, depleting electron transport components, and inhibiting the growth of rapidly dividing tumor cells. This study identifies argyrin B as an antibacterial and cytotoxic agent that inhibits EF-G, a target which is evolutionarily conserved from bacteria to yeast to mammalian cells

Antibacterial and Solubility Optimization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) provided access to analogues in the Northern region (C2–C10). Selective hydrolysis of the C10 amide of lead compound <b>2</b> and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., <b>3</b>) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster <i>C. difficile</i> models of disease. Optimal efficacy in the hamster model of <i>C. difficile</i> was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility