The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.

clinicaltrials.gov Identifier: NCT00129545.

When multilevel models are estimated from survey data derived using multistage sampling, unequal selection probabilities at any stage of sampling may induce bias in standard estimators, unless the sources of the unequal probabilities are fully controlled for in the covariates. This paper proposes alternative ways of weighting the estimation of a two-level model by using the reciprocals of the selection probabilities at each stage of sampling. Consistent estimators are obtained when both the sample number of level 2 units and the sample number of level 1 units within sampled level 2 units increase. Scaling of the weights is proposed to improve the properties of the estimators and to simplify computation. Variance estimators are also proposed. In a limited simulation study the scaled weighted estimators are found to perform well, although non-negligible bias starts to arise for informative designs when the sample number of level 1 units becomes small. The variance estimators perform extremely well. The procedures are illustrated using data from the survey of psychiatric morbidity.

A genomics‐based approach was used to identify the entire gene complement of putative two‐component signal transduction systems (TCSTSs) in Streptococcus pneumoniae. A total of 14 open reading frames (ORFs) were identified as putative response regulators, 13 of which were adjacent to genes encoding probable histidine kinases. Both the histidine kinase and response regulator proteins were categorized into subfamilies on the basis of phylogeny. Through a systematic programme of mutagenesis, the importance of each novel TCSTS was determined with respect to viability and pathogenicity. One TCSTS was identified that was essential for the growth of S. pneumoniaeThis locus was highly homologous to the yycFG gene pair encoding the essential response regulator/histidine kinase proteins identified in Bacillus subtilis and Staphylococcus aureus. Separate deletions of eight other loci led in each case to a dramatic attenuation of growth in a mouse respiratory tract infection model, suggesting that these signal transduction systems are important for the in vivo adaptation and pathogenesis of S. pneumoniae. The identification of conserved TCSTSs important for both pathogenicity and viability in a Gram‐positive pathogen highlights the potential of two‐component signal transduction as a multicomponent target for antibacterial drug discovery.

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