Design, synthesis and biological evaluation of non-natural modulators of quorum sensing in Pseudomonas aeruginosa

Many species of bacteria employ a mechanism of intercellular communication known as quorum sensing which is mediated by small diffusible signalling molecules termed autoinducers. The most common class of autoinducer used by Gram-negative bacteria are N-acylated-L-homoserine lactones (AHLs). Pseudomonas aeruginosa is a clinically important bacterium which is known to use AHL-mediated quorum sensing systems to regulate a variety of processes associated with virulence. Thus the selective disruption of AHL-based quorum sensing represents a strategy to attenuate the pathogenicity of this bacterium. Herein we describe the design, synthesis and biological evaluation of a collection of structurally novel AHL mimics. A number of new compounds capable of modulating the LasR-dependent quorum sensing system of P. aeruginosa were identified, which could have value as molecular tools to study and manipulate this signalling pathway. Worthy of particular note, this research has delivered novel potent quorum sensing antagonists, which strongly inhibit the production of virulence factors in a wild type strain of this pathogenic bacterium.     

1,2‐Ph2‐9‐I‐1,2‐closo‐C2B10H9

The title compound, 9‐iodo‐1,2‐di­phenyl‐1,2‐dicarba‐closo‐dodecaborane(9), C₁₄H₁₉B₁₀I, has the expected pseudo‐icosahedral cluster geometry, with a cage C—C distance of 1.724 (4) Å, comparable to that in the non‐iodinated parent. However, the twist angles, θ, of the phenyl rings are 2.1 (6) and 27.6 (5)°, the latter being unusually large.     

The certification of SRM 1546 – Meat Homogenate, a new reference material for nutrients in a high protein, high fat matrix

In response to reference material needs expressed by the food industry and government regulators, the National Institute of Standards and Technology (NIST) has developed a new Standard Reference Material (SRM) consisting of a canned meat product with certified and reference values for a large number of constituents. SRM 1546 Meat Homogenate consists of a mixture of finely ground pork and chicken prepared and canned by a commercial process. NIST determined the concentration levels of cholesterol, sodium, calcium, iron, and seven fatty acids in this SRM using well defined methods and procedures. These analytes as well as 34 other constituents or properties were determined in an interlaboratory comparison exercise involving 21 laboratories, most of which are associated with the National Food Processors Association (NFPA) Food Industry Analytical Chemists Subcommittee (FIACS). From statistical analysis of the data, NIST assigned certified concentrations for the eleven analytes measured at NIST and reference concentrations for the proximates, six additional fatty acids, seven minerals, and seven water-soluble vitamins. Information values without uncertainties are provided for the concentrations of six additional constituents for which the uncertainties could not adequately be assessed. SRM 1546 will provide laboratories with a means to evaluate the accuracy of the methods they use to assign nutrient levels to processed meats and similar products. Received: 11 October 2000 / Revised: 15 December 2000 / Accepted: 21 December 2000     

Crystal engineering with heteroboranes. I. 1-Carboxy-1,2-dicarba-closo-dodecaborane(11)

The title compound, C₃H₁₂B₁₀O₂ or 1-COOH-1,2-closo-C₂B₁₀H₁₁, forms centrosymmetric dimers through intermolecular hydrogen bonding between the carboxylic acid groups, resulting in the formation of an eight-membered ring [R(8)]. The C=O bond of the carboxylic acid group almost eclipses the unsubstituted cage C atom, with a C—C—C—O torsion angle of 2.6 (2)°.     

Efficient Global Optimization of Expensive Black-Box Functions

In many engineering optimization problems, the number of function evaluations is severely limited by time or cost. These problems pose a special challenge to the field of global optimization, since existing methods often require more function evaluations than can be comfortably afforded. One way to address this challenge is to fit response surfaces to data collected by evaluating the objective and constraint functions at a few points. These surfaces can then be used for visualization, tradeoff analysis, and optimization. In this paper, we introduce the reader to a response surface methodology that is especially good at modeling the nonlinear, multimodal functions that often occur in engineering. We then show how these approximating functions can be used to construct an efficient global optimization algorithm with a credible stopping rule. The key to using response surfaces for global optimization lies in balancing the need to exploit the approximating surface (by sampling where it is minimized) with the need to improve the approximation (by sampling where prediction error may be high). Striking this balance requires solving certain auxiliary problems which have previously been considered intractable, but we show how these computational obstacles can be overcome.     

Synthesis of an mRNA fragment of alanyl-tRNA synthetase gene in Escherichia coli using the 6-methyl-3-pyridyl group for protection of the imide functions of uridine and guanosine

The synthesis of 5'-GpGpUpGpU-3' is reported to demonstrate the synthetic use of the 6-methyl-3-pyridyl group for the protection of the O-4 and O-6 imide functions of uridine and guanosine, respectively. The 2'- and 5'-hydroxyl functions of the key intermediates were protected with two acid-labile groups: 3-methoxy-1,5-dicarbomethoxypentane-3-yl (MDMP) and 9-(4-octadecyloxyphenyl)xanthen-9-yl (C18Px), respectively. The internucleotide phosphotriesters were protected with 2-chlorophenyl and the 9-fluorenylmethyl group was employed for 3'-terminal phosphate protection.