The identification and characterization of novel antibacterial compounds via target-based and whole cell screening approaches

The emergence of multidrug-resistant bacterial infections in both the clinical setting and the community has created an environment in which the development of novel antibacterial compounds is necessary to keep dangerous infections at bay. While the derivatization of existing antibiotics by pharmaceutical companies has so far been successful at achieving this end, this strategy is short-term, and the discovery of antibacterials with novel scaffolds would be a greater contribution to the fight of multidrug-resistant infections. Described herein is the application of both target-based and whole cell screening strategies to identify novel antibacterial compounds. In a target-based approach, we sought small-molecule disruptors of the MazEF toxin-antitoxin protein complex. A lack of facile, continuous assays for this target required the development of a fluorometric assay for MazF ribonuclease activity. This assay was employed to further characterize the activity of the MazF enzyme and was used in a screening effort to identify disruptors of the MazEF complex. In addition, by employing a whole cell screening approach, we identified two compounds with potent antibacterial activity. Efforts to characterize the in vitro antibacterial activities displayed by these compounds and to identify their modes of action are described.

Identification and characterization of shallow impurity states in gallium arsenide and indium phosphide using photothermal ionization spectroscopy

A model of far infrared (FIR) dielectric response of shallow impurity states in a semiconductor has been developed and is presented for the specific case of the shallow donor transitions in high purity epitaxial GaAs. The model is quite general, however, and should be applicable with slight modification, not only to shallow donors in other materials such as InP, but also to shallow acceptors and excitons. The effects of the enormous dielectric response of shallow donors on the FIR optical properties of reflectance, transmittance, and absorptance, and photoconductive response of high purity epitaxial GaAs films are predicted and compared with experimental photothermal ionization spectra. The model accounts for many of the peculiar features that are frequently observed in these spectra, one of which was the cause of erroneous donor identifications in the early doping experiments. The model also corrects some commonly held misconceptions concerning photo-thermal ionization peak widths and amplitudes and their relationships to donor and acceptor concentrations. These corrections are of particular relevance to the proper interpretation of photothermal ionization spectra in the study of impurity incorporation in high purity epitaxial material. The model also suggests that the technique of FIR reflectance, although it has not been widely employed, should be useful in the study of shallow impurities in semiconductors.