Dennis Keith

Discovery of a potent and selective series of pyrazole bacterial methionyl-tRNA synthetase inhibitors.

Starting with a micromolar lead identified from high-throughput screening, a series of pyrazoles were discovered with significantly improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase.

A series of quinoline analogues as potent inhibitors of C. albicans prolyl tRNA synthetase

A series of quinoline inhibitors of C. albicans prolyl tRNA synthetase was identified. The most potent analogue, 2-(4-bromo-phenyl)-6-chloro-8-methyl-4-quinolinecarboxylic acid, showed IC50 = 5 nM (Ca. ProRS) with high selectivity over the human enzyme.

The identification of quality antibacterial drug discovery targets: a case study with aminoacyl-tRNA synthetases

Although there is a clearly established need for new antibiotics, the route to their discovery is anything but clear or defined. One possible approach is target-based drug discovery. Adhering to this strategy, appropriate targets must first be selected. Even this early stage step in the process is not straightforward. As described here, numbers of genomics targets are available and a subset of those have been linked to infection. However, only a further subset of these targets will prove amenable to drug discovery. Here we profile two approaches to identify quality drug discovery targets from within a family of enzymes known as aminoacyl-tRNA synthetases. Targets were selected based on (i) high throughput screening data or (ii) protein sequence similarity analyses. The merits of each approach are discussed. Although some measure of success was achieved using sequence similarity to prioritise targets, high throughput screening data and the subsequent profiling of hits resulted in the selection of higher quality targets for further study.

Structure–Activity Relationship Studies of a Series of Semisynthetic Lipopeptides Leading to the Discovery of Surotomycin, a Novel Cyclic Lipopeptide Being Developed for the Treatment of Clostridium difficile-Associated Diarrhea

Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 μg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.

Reduced pulmonary surfactant interaction of daptomycin analogs via tryptophan replacement with alternative amino acids.

Daptomycin was shown to interact in vitro with pulmonary surfactant leading to reduction of its antibacterial activity. We report herein the preparation and anti-staphylococcal activity of a series of daptomycin analogs with reduced pulmonary surfactant interaction by replacing tryptophan with various amino acids.