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.

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.