Domestic dogs (Canis familiaris) were administered progressive elimination tasks in which they had to visit and deplete either 3 or 4 baited sites. They were brought back to the starting point after each visit.  When administered a 4-choice task with small angular deviation between adjacent targets, the dogs chose first an inner target (e.g., right inner target) and the opposite outer target (e.g., the left target) as a second correct choice.  So they relied on divergence; that is they chose the farthest target as the next choice.  Varying angular deviation did not modulate divergence.  Decreasing the number of targets (3-choice task, Experiment 2) did relax divergence, though target selection was not totally random.  The dogs still chose as a first choice an inner target (i.e., the middle target) when selecting the most divergent patterns of elimination. Finally, in Experiment 3, the dogs were administered a 3-choice task with large angular deviation but in which all targets had been hidden.  The dogs chose first an outer target (i.e., right or left)) and the other outer target as the second correct choice.  That is they relied on divergence.  The results suggest that divergence is the outcome of a flexibility/cognitive load tradeoff when facing novelty and uncertainty.

Bacterial resistance represents a major health problem worldwide and there is an urgent need to develop first-in-class compounds directed against new therapeutic targets. We previously developed a drug-discovery platform to identify new antimicrobials able to disrupt the protein-protein interaction between the β' subunit and the σ⁷⁰ initiation factor of bacterial RNA polymerase, which is essential for transcription. As a follow-up to such work, we have improved the discovery strategy to make it less time-consuming and more cost-effective. This involves three sequential assays, easily scalable to a high-throughput format, and a subsequent in-depth characterization only limited to hits that passed the three tests. This optimized workflow, applied to the screening of 5360 small molecules from three synthetic and natural compound libraries, led to the identification of six compounds interfering with the β'-σ⁷⁰ interaction, and thus was capable of inhibiting promoter-specific RNA transcription and bacterial growth. Upon supplementation with a permeability adjuvant, the two most potent transcription-inhibiting compounds displayed a strong antibacterial activity against Escherichia coli with minimum inhibitory concentration (MIC) values among the lowest (0.87-1.56 μM) thus far reported for β'-σ PPI inhibitors. The newly identified hit compounds share structural feature similarities with those of a pharmacophore model previously developed from known inhibitors.