Microbiological profile, preclinical pharmacokinetics and efficacy of CRS0393, a novel antimycobacterial agent targeting MmpL3.

The benzothiazole amide CRS0393 demonstrated excellent in vitro activity against nontuberculous mycobacteria (NTM), including M. abscessus isolates from cystic fibrosis (CF) patients, with minimum inhibitory concentrations (MICs) of ≤0.03-0.

Potency of the novel PolC DNA polymerase inhibitor CRS0540 in a disseminated Listeria monocytogenes intracellular hollow-fibre model.

Background: Listeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes.

Methods: Rodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies.

Invertebrate community response to fire and rodent activity in the Mojave and Great Basin Deserts.

Recent increases in the frequency and size of desert wildfires bring into question the impacts of fire on desert invertebrate communities. Furthermore, consumer communities can strongly impact invertebrates through predation and top-down effects on plant community assembly. We experimentally applied burn and rodent exclusion treatments in a full factorial design at sites in both the Mojave and Great Basin deserts to examine the impact that fire and rodent consumers have on invertebrate communities.

Optimization and Lead Selection of Benzothiazole Amide Analogs Toward a Novel Antimycobacterial Agent.

Mycobacteria remain an important problem worldwide, especially drug resistant human pathogens. Novel therapeutics are urgently needed to tackle both drug-resistant tuberculosis (TB) and difficult-to-treat infections with nontuberculous mycobacteria (NTM). Benzothiazole adamantyl amide had previously emerged as a high throughput screening hit against () and was subsequently found to be active against NTM as well.

Discovery of benzothiazole amides as potent antimycobacterial agents.

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity.

MGLM: An R Package for Multivariate Categorical Data Analysis.

Data with multiple responses is ubiquitous in modern applications. However, few tools are available for regression analysis of multivariate counts. The most popular multinomial-logit model has a very restrictive mean-variance structure, limiting its applicability to many data sets.

Database choices in endocrine systematic reviews.

Objective: The choice of bibliographic database during the systematic review search process has been an ongoing conversation among information specialists. With newer information sources, such as Google Scholar and clinical trials registries, we were interested in which databases were utilized by information specialists and systematic review researchers.

Method: We retrieved 144 systematic reviews and meta-analyses from 4 clinical endocrinology journals and extracted all information sources used during the search processes.

Investigating the selectivity of metalloenzyme inhibitors.

The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies.

Development of a high-throughput screen and its use in the discovery of Streptococcus pneumoniae immunoglobulin A1 protease inhibitors.

Streptococcus pneumoniae relies on a number of virulence factors, including immunoglobulin A1 protease (IgA1P), a Zn(2+) metalloprotease produced on the extracellular surface of the bacteria, to promote pathogenic colonization. IgA1P exhibits a unique function, in that it catalyzes the proteolysis of human IgA1 at its hinge region to leave the bacterial cell surface masked by IgA1 Fab, enabling the bacteria to evade the host's immune system and adhere to host epithelial cells to promote colonization. Thus, S.

Antagonism of a zinc metalloprotease using a unique metal-chelating scaffold: tropolones as inhibitors of P. aeruginosa elastase.

Tropolone emerged from the screening of a chelator fragment library (CFL) as an inhibitor of the Zn(2+)-dependent virulence factor, Pseudomonas aeruginosa elastase (LasB). Based on this initial hit, a series of substituted tropolone-based LasB inhibitors was prepared, and a compound displaying potent activity in vitro and in a bacterial swarming assay was identified. Importantly, this inhibitor was found to be specific for LasB over other metalloenzymes, validating the usage of tropolone as a viable scaffold for identifying first-in-class LasB inhibitors.

The catalytic enantioselective total synthesis of (+)-liphagal.

[Image: see text] : The first catalytic enantioselective total synthesis of the meroterpenoid natural product (+)-liphagal is disclosed. The approach showcases a variety of technology including enantioselective enolate alkylation, a photochemical alkyne-alkene [2+2] reaction, microwave-assisted metal catalysis, and an intramolecular aryne capture cyclization reaction. Pivotal to the successful completion of the synthesis was a sequence involving ring expansion from a [6-5-4] tricycle to a [6-7] bicyclic core followed by stereoselective hydrogenation of a sterically occluded tri-substituted olefin to establish the trans homodecalin system found in the natural product.

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition.

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Progress toward the total synthesis of (+/-)-actinophyllic acid.

This paper describes ongoing progress toward the synthesis of the novel indole alkaloid actinophyllic acid via a synthetic strategy that allows for the installation of all C-atoms (highlighted in red) requisite for completion of a total synthesis.