In Vitro Resistance Development to Nemonoxacin in Streptococcus pneumoniae: A Unique Profile for a Novel Nonfluorinated Quinolone.

Selection of resistant strains in Streptococcus pneumoniae was studied in vitro with nemonoxacin, a novel nonfluorinated quinolone (NFQ), in comparison with quinolone benchmarks, ciprofloxacin, garenoxacin, and gatifloxacin. In stepwise resistance selection studies, a 256-fold loss of potency was observed after three to four steps of exposure to ciprofloxacin or garenoxacin. In contrast, the loss of potency was limited to eightfold after three steps of exposure to nemonoxacin and repeated attempts to isolate highly resistant organisms after four steps of exposure yielded isolates that could not be subcultured in liquid medium.

Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors.

In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N-terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents.

Development and use of a high-throughput bacterial DNA gyrase assay to identify mammalian topoisomerase II inhibitors with whole-cell anticancer activity.

A high-throughput screen (HTS) was developed and used to identify inhibitors of bacterial DNA gyrase. Among the validated hits were 53 compounds that also inhibited mammalian topoisomerase II with IC(50) values of <12.5 micro g/mL for 51 of them.

Synthesis and biological testing of non-fluorinated analogues of levofloxacin.

Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.