Tobramycin and Nebramine as Pseudo‐oligosaccharide Scaffolds for the Development of Antimicrobial Cationic Amphiphiles

Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo‐oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. Herein, we report the design and synthesis of cationic amphiphiles derived from the pseudo‐trisaccharide aminoglycoside tobramycin and its pseudo‐disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure–activity relationships were studied. Several cationic amphiphiles showed marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against all of the tested strains of bacteria; furthermore, against several of the tested strains, this compound was well over an order of magnitude more potent than the parent antibiotic tobramycin, the membrane‐targeting antimicrobial peptide mixture gramicidin D, and the cationic lipopeptide polymyxin B, which are in clinical use.     

Antifungal Imidazole‐Decorated Cationic Amphiphiles with Markedly Low Hemolytic Activity

Herein we report that an imidazole‐decorated cationic amphiphile derived from the pseudo‐disaccharide nebramine has potent antifungal activity against strains of Candida glabrata pathogens. In combination with the natural bis‐benzylisoquinoline alkaloid tetrandrine the reported antifungal cationic amphiphile demonstrated synergistic antifungal activity against Candida albicans pathogens. This unique membrane disruptor caused no detectible mammalian red blood cell hemolysis at concentrations up to more than two orders of magnitude greater than its minimal inhibitory concentrations against the tested C. glabrata strains. We provide evidence that potency against C. glabrata may be associated with differences between the drug efflux pumps of C. albicans and C. glabrata. Imidazole decorated‐cationic amphiphiles show promise for the development of less toxic membrane‐disrupting antifungal drugs and drug combinations.     

2 Higgs or not 2 Higgs

Motivated by recent results from the LHC experiments, we analyze Higgs couplings in two Higgs doublet models with an approximate PQ   symmetry. Models of this kind can naturally accommodate sizable modifications to Higgs decay patterns while leaving production at hadron colliders untouched. Near the decoupling limit, we integrate out the heavy doublet to obtain the effective couplings of the SM-like Higgs and express these couplings in a physically transparent way, keeping all orders in (_mh/_mH)$(m_h/m_H)$ for small PQ breaking. Considering supersymmetric models, we show that the effects on the Higgs couplings are considerably constrained.     

Acyclic systems of representatives and acyclic colorings of digraphs

A natural digraph analog of the graph theoretic concept of “an independent set” is that of “an acyclic set of vertices,” namely a set not spanning a directed cycle. By this token, an analog of the notion of coloring of a graph is that of decomposition of a digraph into acyclic sets. We extend some known results on independent sets and colorings in graphs to acyclic sets and acyclic colorings of digraphs. In particular, we prove bounds on the topological connectivity of the complex of acyclic sets, and using them we prove sufficient conditions for the existence of acyclic systems of representatives of a system of sets of vertices. These bounds generalize a result of Tardos and Szabó. We prove a fractional version of a strong‐acyclic‐coloring conjecture for digraphs. © 2008 Wiley Periodicals, Inc. J Graph Theory 59: 177–189, 2008     

Sending information to interactive receivers playing a generalized prisoners’ dilemma

Consider the problem of information disclosure for a planner who faces two agents interacting in a state-dependent multi-action prisoners’ dilemma. We find conditions under which the planner can make use of his superior information by disclosing some of it to the agents, and conditions under which such information leakage is not possible. Although the problem is entirely symmetric, the planner’s only way to reveal part of the information is based on creating asymmetries between the two agents by giving them different pieces of information. We also find conditions under which such partially informative equilibria are the planner’s best equilibria.     

Aerobic oxidation of benzylic alcohols with solid alkaline metal hydroxides

Solid alkaline metal hydroxides displayed high catalytic activity and full selectivity in the aerobic oxidation of benzylic alcohols in a non-polar medium. The activity of the solid bases, in decreasing order of reactivity, was KOH > NaOH ≫ LiOH. Water, which is the only by-product of the reaction, plays a crucial role in KOH deactivation by converting the crystal phase of KOH to KOH · H₂O, as confirmed by XRD measurements.     

Inherently Emissive Puromycin Analogues for Live Cell Labelling

Puromycin derivatives containing an emissive thieno[3,4-d]-pyrimidine core, modified with azetidine and 3,3-difluoroazetidine as Me₂N surrogates, exhibit translation inhibition and bactericidal activity similar to the natural antibiotic. The analogues are capable of cellular puromycylation of nascent peptides, generating emissive products without any follow-up chemistry. The 3,3-difluoroazetidine-containing analogue is shown to fluorescently label newly translated peptides and be visualized in both live and fixed HEK293T cells and rat hippocampal neurons.