Infection caused by Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is very common in communities and hospitals, which poses a great challenge to human health. Therefore, increasing attention has been paid to finding effective antimicrobial agents. Mansonone F is a natural compound which has an oxaphenalene skeleton and anti-S. aureus activity, but its sources are limited and its synthesis is difficult. Thus, IG1, a C9-substituent mansonone F analog, was assessed for its activity against Staphylococcus aureus and its mechanism of action was investigated. Antimicrobial susceptibility assays showed that IG1 has strong antibacterial activity against S. aureus, including MRSA, with minimum inhibitory concentrations (MICs) ranging from 0.5 to 2 μg/mL, which were very close to those of vancomycin, and these changed little, even with an increase in the amount of the inoculum. To further explore the antibacterial properties of IG1, time–kill experiments were conducted. Compared with vancomycin and moxifloxacin, treatment with different concentrations of IG1 reduced the viability of organisms in a very similar manner and the reduction was not significant, which indicated that IG1 is a potentially strong anti-S. aureus agent. Finally, the antibacterial mechanism was analyzed, with flow cytometric analysis revealing that IG1 treatment resulted in a time-dependent decrease in the DNA content of S. aureus. Transmission electron microscopy (TEM) analysis showed that very few dividing cells could be found and the cell wall was damaged in the field of IG1-treated cells. These results indicate that IG1 is a potential new antibacterial agent against S. aureus, including MRSA.

Studies have shown that NMDA receptors (NMDARs) can mediate multiple forms of synaptic plasticity, including induction of long-term enhancement (LTP) or long- term inhibition (LTD)^[1]. The NR2A subunit has a strong correlation with LTP production and can in turn induce learning-related behaviors. For example, NR2A knockout (NR2A-/-) mice exhibit some significant memory-deficit behaviors^[2]. Therefore, it can be used as a valuable model for exploring the pathways and mechanisms involved in memory encoding and may also inform the treatment of memory disorders. The cholecystokinin (CCK) neuronal ensemble has been shown to be involved in memory imprinting function in multiple brain regions^[3–6]. However, it remains unclear whether pharmacological modulation of CCK can improve memory- related deficits in NR2A knockout animals. This study utilizes a novel object recognition task and a context-dependent fear learning paradigm to evaluate the role of CCK in memory generalization in NR2A-KO mice. Our results show that NR2A- KO mice exhibit significantly impaired discrimination, learning, and fear conditioning. Notably, CCK manipulation enhanced the associative memory generalization and discrimination abilities of these animals. Similarly, we performed electrophysiological studies, including in vitro multichannel recordings, to examine the effects of CCK on LTP-induction in the cortex and hippocampus. Notably, CCK restored LTP in the cortex and hippocampus in NR2A-KO mice. In addition, monitoring of calcium (Ca2+) activity during memory recall using fiber photometry in the auditory cortex (AC) showed a significant enhancement of calcium signal after CCK administration. To test our hypothesis that the deletion of NR2A may affect the release of CCK, we used a specific CCKBR sensor system combined with optogenetic viruses to detect the release of CCK after high-frequency stimulation of the CCK axon terminus projected by LEC to AC, but the release of CCK was blocked by the application of NR2A antagonists. These results suggest that CCK not only compensates for the loss of LTP in NR2A-KO mice, but also improves the corresponding memory-deficit- like behavior in animals. Overall, our findings identify CCK as a promising target for the treatment of memory deficits and elucidate its role in memory encoding mechanisms.