Martin, James K; Sheehan, Joseph P; Bratton, Benjamin P; Moore, Gabriel M; Mateus, André; Li, Sophia Hsin-Jung; Kim, Hahn; Rabinowitz, Joshua D; Typas, Athanasios; Savitski, Mikhail M; Wilson, Maxwell Z; Gitai, Zemer
Abstract:
The rise of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably-low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing MRSA persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrheae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.
It is well known that formation of new episodic memories depends on hippocampus, but in real-life settings (e.g., conversation), hippocampal amnesics can utilize information from several minutes earlier. What neural systems outside hippocampus might support this minutes-long retention? In this study, subjects viewed an audiovisual movie continuously for 25 min; another group viewed the movie in 2 parts separated by a 1-day delay. Understanding Part 2 depended on retrieving information from Part 1, and thus hippocampus was required in the day-delay condition. But is hippocampus equally recruited to access the same information from minutes earlier? We show that accessing memories from a few minutes prior elicited less interaction between hippocampus and default mode network (DMN) cortical regions than accessing day-old memories of identical events, suggesting that recent information was available with less reliance on hippocampal retrieval. Moreover, the 2 groups evinced
reliable but distinct DMN activity timecourses, reflecting differences in information carried in these regions when Part 1 was recent versus distant. The timecourses converged after 4 min, suggesting a time frame over which the continuous-viewing group may have relied less on hippocampal retrieval. We propose that cortical default mode regions can intrinsically retain real-life episodic information for several minutes.
Small changes in word choice can lead to dramatically different interpretations of narratives. How does the brain accumulate and integrate such local changes to construct unique neural representations for different stories? In this study we created two distinct narratives by changing only a few words in each sentence (e.g. “he” to “she” or “sobbing” to “laughing”) while preserving the grammatical structure across stories. We then measured changes in neural responses between the two stories. We found that the differences in neural responses between the two stories gradually increased along the hierarchy of processing timescales. For areas with short integration windows, such as early auditory cortex, the differences in neural responses between the two stories were relatively small. In contrast, in areas with the longest integration windows at the top of the hierarchy, such as the precuneus, temporal parietal junction, and medial frontal cortices, there were large differences in neural responses between stories. Furthermore, this gradual increase in neural difference between the stories was highly correlated with an area’s ability to integrate information over time. Amplification of neural differences did not occur when changes in words did not alter the interpretation of the story (e.g. “sobbing” to “crying”). Our results demonstrate how subtle differences in words are gradually accumulated and amplified along the cortical hierarchy as the brain constructs a narrative over time.
