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We synthesized a range of PQS (Pseudomonas quinolone signal; 2-heptyl-3-hydroxy-4(1H)-quinolone) analogues and tested them for their ability to stimulate MvfR-dependent pqsA transcription, MvfR-independent pyoverdine production, and membrane vesicle production. The structure-activity profile of the PQS analogues was different for each of these phenotypes. Certain inactive PQS analogues were also found to strongly synergize PQS-dependent pyoverdine production. doi: 10.1128/JB.00081-10

ABSTRACT Many Gram-negative bacteria employ a mechanism of cell cell communication known as quorum sensing (QS). The role of QS is to enable the cells in a culture to coordinate [...]

Serratia marcescens is an important cause of opportunistic human infections. Many, but not all, strains produce prodigiosin, a secondary metabolic, red-pigment antibiotic, the biosynthesis of which is directed by the pig gene cluster. Quorum sensing (QS) involves the production and detection of chemical signal molecules as a means to regulate gene expression in response to population cell density. Several strains of S. marcescens have previously been shown to possess an N-acyl-L-homoserine lactone (aHSL) QS system. This study aimed to determine the impact of introducing, by phage-mediated horizontal gene transfer, a biosynthetic gene cluster (pig) and a regulatory locus (aHSL QS) into strains lacking the respective trait. The pig cluster from S. marcescens ATCC 274 (Sma 274) was transferred to the non-pigmented strain, S. marcescens strain 12 (Sma 12). In the engineered strain, pigment was expressed and brought under the control of the recipient's native regulatory systems (aHSL QS and luxS). Moreover, transfer of the aHSL locus from Sma 12 to the non-QS Sma 274 resulted in the imposition of aHSL control onto a variety of native traits, including pigment production. In addition, during this study, the QS regulon of the clinical strain, Sma 12, was characterized, and some novel QS-regulated traits in S. marcescens were identified. The results have implications for the evolution and dissemination of biosynthetic and QS loci, illustrating the genetic modularity and ease of acquisition of these traits and the capacity of phages to act as vectors for horizontal gene transfer.

The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment, respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)[P.sub.2], suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer. drug discovery | drug target identification | proteomics | diabetes

A number of bacteria, including some significant pathogens, utilize N-acylhomoserine lactones (AHLs) as quorum sensing signals. There is considerable interest in the therapeutic potential of disrupting quorum sensing. Recently, a number of bacteria have been identified which are capable of enzymic inactivation of AHLs. These enzymes show considerable promise as 'quenchers' of quorum sensing. However, the assumption that the natural function of these enzymes is to disrupt or modulate quorum sensing has yet to be established. This review surveys the progress made to date in this field and examines what implications these findings have for out understanding of the role played by these enzymes in vivo.

The development, scope and mechanism of general, efficient and atropdiastereoselective reactions leading to compounds having biaryl containing medium rings are reported. The process described outlines a pathway that will contribute to a systematic and comprehensive approach to exploring biology (chemical genetics).

A newly developed amide-containing receptor for [Zn.sup.2+], combined with a naphthalimide fluorophore, termed ZTRS is presented. The developed ZTRS could be applied to image intracellular [Zn.sup.2+] ions in the presence of iron ions and to detect zinc ions during the development of living zebrafish embryos.

It has been possible to identify readily synthesized substrates that experience two forms of medium ring-forming reactions producing two classes of complex structures, one patterned after the biaryl natural products and the other a metal-inserted variant.

The advantage of the DOS approach is that it efficiently creates structurally diverse molecules whose molecular masses are usually close to those of drug-like compounds (5,6) (Fig. 2b). Moreover, DOS [...]