Discovery and optimization of tetrahydroacridine derivatives as a novel class of antibiotics against multidrug-resistant Gram-positive pathogens by targeting type I signal peptidase and disrupting bacterial membrane
Xiaolin Lu , Xianghan Xu , Yushi Ding , Xin Gong , Liqin Ming , Xingyang Dai , Congying Gu , Jiayi Wang , Jiaqi Zhao , Mengkang Gao , Hao Yin , Zhi Wang , Xiaoming Wang , Liping Wang , Dayong Zhang , Menghan Zhang , Jinhu Huang
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引用次数: 0
Abstract
Increasing antimicrobial resistance underscores the urgent need for new antibiotics with unique mechanisms. Type I signal peptidase (SPase I) is crucial for bacterial survival and a promising target for antibiotics. Herein we designed and synthesized innovative tetrahydroacridine-9-carboxylic acid derivatives by optimizing the initial hit compound SP11 based on virtual screening. Structure-activity relationship (SAR) studies and bioactivity assessments identified compound C09 as a standout, showing excellent in vitro antimicrobial activity against MRSA and other multidrug-resistant Gram-positive pathogens. C09 targets SPase I with a favorable affinity, disrupts bacterial cell membranes, and eradicates biofilms, reducing resistance risk. In vivo tests in a murine MRSA skin infection model demonstrated significant efficacy. Additionally, C09 has good liver microsome metabolic stability, safe hemolytic activity and mammalian cytotoxicity, as well as a good in vivo safety profile. Overall, our findings highlight the potential of tetrahydroacridine-9-carboxylic acid derivatives as a novel class of antibiotics against multidrug-resistant Gram-positive bacteria.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.