In-plane parallel scanning: a microarray technology for point-of-care testing.

A new microarray technology is described for rapid, inexpensive, multiplex diagnostics assays. Referred to as "in-plane parallel scanning" (IPPS), this technology replaces expensive laser scanning with a grid of 100-µm-wide waveguides embedded in the chip's substrate, enabling real-time quantification of molecular complex formation on the chip's surface. Compared to conventional microarray technology, IPPS has advantages of shorter assay time and lower instrument cost and complexity so that the platform can potentially be used in point-of-care (POC) settings. Two different chip formats are described: a low-density microarray with 10 sensing wells (IPPS-10) and a medium-density one with 100 sensing wells (IPPS-100). Performance was evaluated in two different proof-of-principle immunoassays: interleukin-1ß (IL-1ß) and Clostridium difficile toxin A. The two assays gave similar limits of detection of 0.67 and 0.94 pM, respectively. A saturation kinetics model described the sensor response with apparent dissociation constants of 511 pM for IL-1ß and 6.47 nM for C. difficile toxin A toxoid. The multiplexing capabilities of the IPPS technology were also demonstrated in a multiplex assay for both analytes on the same IPPS-10 chip. Based on these results, the IPPS technology holds promise for translating diagnostic microarrays into near-patient environments.

DNA binding ligands targeting drug-resistant bacteria: structure, activity, and pharmacology.

We describe the lead optimization and structure-activity relationship of DNA minor-groove binding ligands, a novel class of antibacterial molecules. These compounds have been shown to target A/T-rich sites within the bacterial genome and, as a result, inhibit DNA replication and RNA transcription. The optimization was focused on N-terminal aromatic heterocycles and C-terminal amines and resulted in compounds with improved in vivo tolerability and excellent in vitro antibacterial potency (MIC >/= 0.031 microg/mL) against a broad range of Gram-positive pathogens, including drug-resistant strains such as methicillin-resistant Stapylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus faecalis (VRE). In a first proof-of-concept study, a selected compound (35) showed in vivo efficacy in a mouse peritonitis model against methicillin-sensitive S. aureus infection with an ED(50) value of 30 mg/kg.

DNA binding ligands targeting drug-resistant Gram-positive bacteria. Part 1: Internal benzimidazole derivatives.

Novel DNA minor-groove binding ligands with a promising antibacterial profile are described. Apart from excellent in vitro potency against multiple Gram-positive bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-intermediate Streptococcus pneumoniae (PISP), a small subset of compounds was active against Gram-negative bacteria such as Escherichia coli (E. coli).