Bichromatic phase-control of interfering Autler-Townes spectra

We propose a new scheme to control the shape of the Autler-Townes (AT) doublet in the photoelectron spectrum from atomic resonance-enhanced multiphoton ionization (REMPI). The scheme is based on the interference of two AT doublets created by ionization of the strongly driven atom from the ground and the resonantly excited state using tailored bichromatic femtosecond (fs) laser pulses. In this scheme, the quantum phase of the photoelectrons is crucial for the manipulation of the AT doublet. The laser polarization state and the relative optical phase between the two colors are used to manipulate the interference pattern. We develop an analytical model to describe the bichromatic REMPI process and provide a physical picture of the control mechanism. To validate the model, the results are compared to an ab initio calculation based on the solution of the 2D time-dependent Schr\"odinger equation for the non-perturbative interaction of an atom with intense polarization-shaped bichromatic fs-laser pulses. Our results indicate that the control mechanism is robust with respect to the laser intensity facilitating its experimental observation.Comment: 13 pages, 5 figure

Orbital angular momentum superposition states in transmission electron microscopy and bichromatic multiphoton ionization

The coherent control of electron beams and ultrafast electron wave packets dynamics have attracted significant attention in electron microscopy as well as in atomic physics. In order to unify the conceptual pictures developed in both fields, we demonstrate the generation and manipulation of tailored electron orbital angular momentum (OAM) superposition states either by employing customized holographic diffraction masks in a transmission electron microscope or by atomic multiphoton ionization utilizing pulse-shaper generated carrier-envelope phase stable bichromatic ultrashort laser pulses. Both techniques follow similar physical mechanisms based on Fourier synthesis of quantum mechanical superposition states allowing the preparation of a broad set of electron states with uncommon symmetries. We describe both approaches in a unified picture based on an advanced spatial and spectral double slit and point out important analogies. In addition, we analyze the topological charge and discuss the control mechanisms of the free-electron OAM superposition states. Their generation and manipulation by phase tailoring in transmission electron microscopy and atomic multiphoton ionization is illustrated on a 7-fold rotationally symmetric electron density distribution.Comment: K. Eickhoff and C. Rathje contributed equally to this wor

Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors

CYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein, we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity toward CYP121, and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesis of promising compounds and led to the identification of favorable features for affinity and/or activity and hit compounds with 2.7-fold improved potency. Mode of action studies show that the hit compounds inhibit substrate conversion and highlighted CYP121 as the main antimycobacterial target of our compounds. Exemplified complex crystal structures of CYP121 with three inhibitors reveal a common binding site. Engaging in both hydrophobic interactions as well as hydrogen bonding to the sixth iron ligand, our compounds block a solvent channel leading to the active site heme. Additionally, we report the first CYP inhibitors that are able to reduce the intracellular replication of M. bovis BCG in macrophages, emphasizing their potential as future drug candidates against TB.Fil: Walter, Isabell. Helmholtz Institute for Pharmaceutical Research Saarland; AlemaniaFil: Adam, Sebastian. Universitat Saarland; AlemaniaFil: Gentilini, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. Twincore; AlemaniaFil: Kany, Andreas M.. Helmholtz Institute for Pharmaceutical Research Saarland; AlemaniaFil: Brengel, Christian. Helmholtz Institute for Pharmaceutical Research Saarland; AlemaniaFil: Thomann, Andreas. Helmholtz Institute for Pharmaceutical Research Saarland; AlemaniaFil: Sparwasser, Tim. Twincore; AlemaniaFil: Köhnke, Jesko. Universitat Saarland; AlemaniaFil: Hartmann, Rolf W.. Universitat Saarland; Alemania. Helmholtz Institute for Pharmaceutical Research Saarland; Alemani

Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors

Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a submicromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

Tackling pseudomonas aeruginosa virulence by a hydroxamic acid-absed LasB inhibitor

In search of novel antibiotics to combat the challenging spread of resistant pathogens, bacterial proteases represent promising targets for pathoblocker development. A common motif for protease inhibitors is the hydroxamic acid function, yet this group has often been related to unspecific inhibition of various metalloproteases. In this work, the inhibition of LasB, a harmful zinc metalloprotease secreted by Pseudomonas aeruginosa, through a hydroxamate derivative is described. The present inhibitor was developed based on a recently reported, highly selective thiol scaffold. Using X-ray crystallography, the lack of inhibition of a range of human matrix metalloproteases could be attributed to a distinct binding mode sparing the S1′ pocket. The inhibitor was shown to restore the effect of the antimicrobial peptide LL-37, decrease the formation of P. aeruginosa biofilm and, for the first time for a LasB inhibitor, reduce the release of extracellular DNA. Hence, it is capable of disrupting several important bacterial resistance mechanisms. These results highlight the potential of protease inhibitors to fight bacterial infections and point out the possibility to achieve selective inhibition even with a strong zinc anchor