Biosynthesis of the corallorazines, a widespread class of antibiotic cyclic lipodipeptides.

Corallorazines are cyclic lipodipeptide natural products produced by the myxobacterium B035. To decipher the basis of corallorazine biosynthesis, the corallorazine nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster was identified and analyzed in detail. Here, we present a model of corallorazine biosynthesis, supported by bioinformatic analyses and investigations on the bimodular NRPS synthesizing the corallorazine core.

Adenylation Domain-Guided Recruitment of Acting Nonheme Monooxygenases in Nonribosomal Peptide Biosynthesis.

Nonheme diiron monooxygenases (NHDMs) interact with nonribosomal peptide synthetase (NRPS) assembly lines to install β-hydroxylations at thiolation-domain-bound amino acids during nonribosomal peptide biosynthesis. The high potential of this enzyme family to diversify the products of engineered assembly lines is disproportionate to the currently small knowledge about their structures and mechanisms of substrate recognition. Here, we report the crystal structure of FrsH, the NHDM which catalyzes the β-hydroxylation of l-leucines during biosynthesis of the depsipeptide G protein inhibitor FR900359.

A Specialized Dehydrogenase Provides l-Phenyllactate for FR900359 Biosynthesis.

d-Phenyllactate (PLA) is a component of the selective Gq protein inhibitor and nonribosomal cyclic depsipeptide FR900359 (FR). Here we report a detailed biochemical investigation of PLA biosynthesis and its incorporation into the natural product FR. The enzyme FrsC, member of the lactate/malate dehydrogenase superfamily, was shown to catalyze the formation of l-PLA from phenylpyruvate.

Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin.

Hypeptin is a cyclodepsipeptide antibiotic produced by Lysobacter sp. K5869, isolated from an environmental sample by the iChip technology, dedicated to the cultivation of previously uncultured microorganisms. Hypeptin shares structural features with teixobactin and exhibits potent activity against a broad spectrum of gram-positive pathogens.

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359.

The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain.

Drug-related problems in head and neck cancer patients identified by repeated medication reviews on consecutive therapy cycles.

Background: Head and neck cancer (HNC) patients are particularly vulnerable to drug-related problems (DRPs) given the toxicity of concomitant chemoradiotherapy (CCRT).

Objective: To investigate the number and type of potential DRPs (pDRPs) in HNC outpatients undergoing five consecutive cycles of CCRT.

Methods: A single-centre, non-randomized, non-interventional, observational study was conducted at the Oncological Outpatient Clinic of the Center for Integrated Oncology at the University Hospital Bonn, Germany.

Interactive Magnetic Catheter Steering With 3-D Real-Time Feedback Using Multi-Color Magnetic Particle Imaging.

Magnetic particle imaging (MPI) is an emerging tomographic method that enables sensitive and fast imaging. It does not require ionizing radiation and thus may be a safe alternative for tracking of devices in the catheterization laboratory. The 3-D real-time imaging capabilities of MPI have been demonstrated in vivo and recent improvements in fast online image reconstruction enable almost real-time data reconstruction and visualization.

In vivo evaluation and proof of radiofrequency safety of a novel diagnostic MR-electrophysiology catheter.

An MR-electrophysiology (EP) catheter is presented that provides full diagnostic EP functionality and a high level of radiofrequency safety achieved by custom-designed transmission lines. Highly resistive wires transmit intracardiac electrograms and currents for intracardiac pacing. A transformer cable transmits the localization signal of a tip coil.

An MR guidewire based on micropultruded fiber-reinforced material.

A novel fiber-reinforced material for the realization of MR guidewires, made using a newly-developed production process, is presented. The MR-safe artificial material provides a high stiffness and torque and allows the production, in a large range of sizes, of nonmetallic MR guidewires with similar mechanical properties as conventional metallic guidewires. Based on this material, a passively visualized MR guidewire has been developed, and was found to conform to existing standards on mechanical stability.

Evaluation of quantum-cascade lasers as local oscillators for infrared heterodyne spectroscopy.

We report experiments evaluating the feasibility of quantum-cascade lasers (QCLs) at mid-infrared wavelengths for use as local oscillators (LOs) in a heterodyne receiver. Performance tests with continuous-wave (cw) lasers around 9.6 and 9.

THIS: a tuneable heterodyne infrared spectrometer.

With the Cologne Tuneable Heterodyne Infrared Spectrometer (THIS) we present a newly developed setup of a transportable heterodyne receiver. Competitiveness with regard to sensitivity, was reached for the first time with a semiconductor laser pumped system. Frequency tuneability of the local oscillator (LO) laser over a wide range of wavelengths is thus provided.

Tuneable Heterodyne Infrared Spectrometer for atmospheric and astronomical studies.

The transportable setup of the Cologne Tuneable Heterodyne Infrared Spectrometer (THIS) is presented. Frequency tuneability over a wide range provided by the use of tuneable diode lasers as local oscillators (LO) allows a variety of molecules in the mid-infrared to be observed. Longtime integration, which is essential for astronomical observations, is possible owing to tight frequency control of the LO with optical feedback from an external cavity.