Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad‐spectrum antibiotic lead was generated with significantly improved activity, including against all Gram‐negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.     

EPR‐Based Approach for the Localization of Paramagnetic Metal Ions in Biomolecules

Metal ions play an important role in the catalysis and folding of proteins and oligonucleotides. Their localization within the three‐dimensional fold of such biomolecules is therefore an important goal in understanding structure–function relationships. A trilateration approach for the localization of metal ions by means of long‐range distance measurements based on electron paramagnetic resonance (EPR) is introduced. The approach is tested on the Cu²⁺ center of azurin, and factors affecting the precision of the method are discussed.     

Determination of the thermal modification degree of beech wood using thermogravimetry

Thermal modification is one of the environmental friendly wood preservation technologies. During this process, changes of the main woody cell wall components occur, which lead to improved dimensional stability, lower hygroscopicity and improvement in biological durability. Several chemical reactions which occur during thermal treatment of wood caused changes in wood properties. During TG measurements, thermal decomposition reactions, which was not completed during previous thermal modification process, continued in wood samples, meaning that more thermally treated samples exhibited lower mass losses in a certain or whole temperature range up to 600 °C. Therefore, mass loss, obtained within selected temperature range, could be used as a marker of previous thermal treatment. The aim of the present work is to evaluate suitability of a thermogravimetric method (TG) for determination of a degree of thermal treatment of beech wood. On the basis of thermally untreated sample and those which were thermally modified at 180, 190, 200, 210, 215 and 220 °C in the absence of oxygen, respectively, and with known values of mass loss during the modification processes, several calibration curves were constructed. They represent mass loss in a certain temperature range during TG measurement versus mass loss during previous thermal modification. In a temperature range from 130 to 300 °C and from 130 to 320 °C under nitrogen atmosphere, a linear dependence was observed; correlation coefficients R ² were 0.87 and 0.91, respectively. In wider temperature range and under air atmosphere, lower correlation coefficients were obtained. High correlation coefficient, higher than 0.95, was observed in a temperature range from 25 to 130 °C under both atmospheres. In this region, dehydration due to rehydration of thermally modified samples occurs. The results of this work were compared with those obtained for Norway spruce.     

Temporal evolution of benzenethiolate SAMs on Cu(100)

The structure and thermal stability of self-assembled monolayers (SAMs) of benzenethiolate (BT) on Cu(100) have been studied by means of thermal desorption spectroscopy (TDS), scanning tunneling microscopy (STM), low-energy electron diffraction (LEED), UV photoelectron spectroscopy (UPS), X-ray photoelectron spectroscopy (XPS), and near-edge X-ray adsorption fine structure spectroscopy (NEXAFS). Vapor deposition at room temperature yields a well-ordered, densely packed c(6 × 2) saturation structure. At room temperature, this film is, however, metastable and transforms via partial decomposition by cleavage of the S-C bond into a less densely packed layer that reveals a coexisting p(2 × 2) phase. Such a transition occurs on a time scale of several days and is accompanied by a reduction of the work function change with respect to the bare Cu(100) surface from Δ? = -0.9 eV for a freshly prepared saturated layer to -0.5 eV for an aged film. TDS experiments exhibit the presence of two distinct desorption channels (dissociative and intact desorption) occurring at different temperatures that reflects a variation of the local Cu-S interaction strength of BT at differently coordinated adsorption sites. Heating to above room temperature causes a rapid degradation and continuous thinning of BT films whereas above 500 K all thiolate species have desorbed or dissociated, leaving a sulfide overlayer behind that is accompanied by a substrate reconstruction. Interestingly, the upright orientation of BT adopted in the saturated monolayer remains almost identical upon heating and demonstrates the absence of downward tilting upon thermally induced thinning of the film.     

First examples of oxaphosphirane pentacarbonylchromium(0) and -molybdenum(0) complexes: synthesis, structures and reactions

Synthesis of the first oxaphosphirane chromium(0) and molybdenum(0) complexes of the type [{(R(1)PCH(R(2))-O}M(CO)(5)] (R(1) = C(5)Me(5)) (8a-e, 15a-e) and (R(1) = CH(SiMe(3))(2)) (9a-e, 16a-e) via reaction of dichloro(organo)- (1, 2, 10, 11) and chloro(organo)phosphane complexes (3,4,12) with lithium bases and aldehydes 7a-e is reported. Furthermore, bicyclic 1,3-oxaphospholane complexes 17 and 18 have been obtained via O-protonation of oxaphosphirane complexes 8a and 15a with HCl. All complexes were characterized by NMR, IR spectroscopic, mass spectrometric investigations and, in addition, single-crystal X-ray structures of complexes 8a-e, 9a,c, 15a,b,e, 16a-c, 17, 18 are presented and discussed.     

Position-resolved determination of trace elements in mandibular gnathobases of the Antarctic copepod <Emphasis Type="Italic">Calanoides acutus</Emphasis> using a multimethod approach

Previous studies have revealed silica formation in the teeth of mandibular gnathobases of copepods while significant amounts of zinc and copper are present, which might improve mechanical stability of the teeth and represent an adaptation to compact food particles. The present study aimed at analysing the distribution and concentration of trace elements in the mandibular gnathobases of females of the Antarctic copepod species Calanoides acutus. Because of the low overall masses of few micrograms per specimen the application of a combination of position-resolved micro-beam techniques was necessary and micro-particle-induced X-ray emission spectrometry and laser ablation inductively coupled plasma mass spectrometry were used to determine Ba, Br, Ca, Cl, Cu, Fe, K, Mg, Na, Ni, P, S, Si and Zn in the samples with μm to sub-μm resolution. Calibration strategies were optimised to fit for the carbonate matrix. The analyses revealed a distinct enrichment of Br, Ca, Fe, K, S, Si and Zn in the teeth of the gnathobases.     

Switchings, extensions, and reductions in central digraphs

A directed graph is called central if its adjacency matrix A satisfies the equation A²=J, where J is the matrix with a 1 in each entry. It has been conjectured that every central directed graph can be obtained from a standard example by a sequence of simple operations called switchings, and also that it can be obtained from a smaller one by an extension. We disprove these conjectures and present a general extension result which, in particular, shows that each counterexample extends to an infinite family.     

Counting all bent functions in dimension eight 99270589265934370305785861242880

Based on the classification of the homogeneous Boolean functions of degree 4 in 8 variables we present the strategy that we used to count the number of all bent functions in dimension 8. There are $$99270589265934370305785861242880 \approx 2^{106}$$ such functions in total. Furthermore, we show that most of the bent functions in dimension 8 are nonequivalent to Maiorana?CMcFarland and partial spread functions.     

Macroscopic investigation of the transient hydrodynamic memory behavior of preparative packed chromatography beds

The goal of the present work was to examine the hydrodynamic behavior of preparative scale packed chromatography beds during long-term cyclical operation at high loads using an experimental set-up with a high resolution measuring device of bed height. One agarose-based resin and one methacrylic-based resin were examined in a 140 mm column. Both resins exhibited hysteresis behavior during compression/relaxation cycles. The hystereses were less pronounced with decreasing hydrodynamic stress rate. The occurrence of hystereses was an indication for hydrodynamic memory behavior of the chromatography packing. During long-term cyclical operation at high loads of the column filled with methacrylic resin, oscillations of the steadily with time decreasing flow rate were observed for the first time. These oscillations were attributed to the viscoelasticity of the polymer particles network representing a system with materials with fading memory. Such nonlinear systems with feed-back are known to exhibit inherent self-oscillations. A decoupling of the two processes of bed compression and decrease of bed permeability was observed. The presented results explain why preparative packed-bed chromatography often yields unsatisfactory reproducible data and why unwanted phenomena like medium wall detachment or other symptoms of deteriorated chromatography beds are frequently observed.