Development and confirmation of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin in a standardized neutropenic murine pneumonia model.

Background: Murine pneumonia models play a fundamental role in the preclinical development of novel compounds seeking an indication for the treatment of pneumonia. It is vital that plasma exposures in these models are not used as a surrogate for exposure in pulmonary epithelial lining fluid (ELF). Herein, human-simulated regimens (HSRs) in both plasma and ELF of meropenem, cefiderocol and tobramycin are described in the standardized COMBINE murine neutropenic pneumonia model.

Cefiderocol pharmacokinetics during acute pulmonary exacerbations in hospitalized adult persons with cystic fibrosis.

Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR).

Total Syntheses of Clausenawallines A and E.

The first total syntheses of glycoborinine, clausenawalline A, and clausenawalline E were achieved. The key step employed a vanadium-catalyzed oxidative coupling of two hydroxycarbazole monomers. High-throughput experimentation was used to identify conditions favoring selective heterocoupling of these monomers that possess similar redox potentials.

Hydrogen Bonding Parameters by Rapid Colorimetric Assessment: Evaluation of Structural Components Found in Biological Ligands and Organocatalysts.

Hydrogen bonding is a key molecular interaction in biological processes, drug delivery, and catalysis. This report describes a high throughput UV-Vis spectroscopic method to measure hydrogen bonding capacity using a pyrazinone sensor. This colormetric sensor reversibly binds to a hydrogen bond donor, resulting in a blue shift as additional equivalents of donor are added.

Modifications to a Biphenolic Antibacterial Compound: Activity against ESKAPE Pathogens.

Forty-four analogs of honokiol, a compound with known antibacterial activity, especially with respect to oral bacteria, were synthesized to explore the structure-activity relationships against the ESKAPE pathogens. Compounds with high therapeutic indices (hemolysis /MIC) were identified. In particular, ester-linked compounds that would be less than environmentally durable than biaryl ether antibacterials such as the broadly used triclosan were found to be active.

Modification of Biphenolic Anti-Bacterial to Achieve Broad-Spectrum Activity.

The Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria, Acinetobacter baumannii, are pathogens responsible for millions of nosocomial infections worldwide. Due to the threat of bacteria evolving resistance to antibiotics, scientists are constantly looking for new classes of compounds to treat infectious diseases. The biphenolic analogs of honokiol that were most potent against oral bacteria had similar bioactivity against MRSA.

Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962).

Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.

Determination of Iodine Content in Dairy Products by Inductively Coupled Plasma Mass Spectrometry.

A probing study to establish a reliable and robust method for determining the iodine concentration using the ELAN DRC II ICP-MS was performed in combination with a sample digestion and filtration step. Dairy products from locally available sources were evaluated to help determine the possibility and need for further evaluations in relation to the U.S.

VU6010608, a Novel mGlu NAM from a Series of -(2-(1-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides.

Herein, we report the structure-activity relationships within a series of mGlu NAMs based on an -(2-(1-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration ( 1.9-5.8 and 0.