Structural Insights into Ceftobiprole Inhibition of Pseudomonas aeruginosa Penicillin-Binding Protein 3.

Ceftobiprole is an advanced-generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, as well as susceptible Gram-negative pathogens, including Pseudomonas sp. pathogens. In the case of Pseudomonas aeruginosa, ceftobiprole acts by inhibiting P. aeruginosa penicillin-binding protein 3 (PBP3). Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3-ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528 to L536 region adopts a conformation previously not observed in PBP3, including partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of ß-lactam-PBP interactions that result in major changes in protein structure, as well as suggesting how to fine-tune current inhibitors and to develop novel inhibitors of this PBP.

Task-driven visual exploration at the foveal scale.

Humans use saccades to inspect objects of interest with the foveola, the small region of the retina with highest acuity. This process of visual exploration is normally studied over large scenes. However, in everyday tasks, the stimulus within the foveola is complex, and the need for visual exploration may extend to this smaller scale. We have previously shown that fixational eye movements, in particular microsaccades, play an important role in fine spatial vision. Here, we investigate whether task-driven visual exploration occurs during the fixation pauses in between large saccades. Observers judged the expression of faces covering approximately 1°, as if viewed from a distance of many meters. We use a custom system for accurately localizing the line of sight and continually track gaze position at high resolution. Our findings reveal that active spatial exploration, a process driven by the goals of the task, takes place at the foveal scale. The scanning strategies used at this scale resemble those used when examining larger scenes, with idiosyncrasies maintained across spatial scales. These findings suggest that the visual system possesses not only a coarser priority map of the extrafoveal space to guide saccades, but also a finer-grained priority map that is used to guide microsaccades once the region of interest is foveated.