AUTHOR=Zhang Fushan , Fang Hui , Zhao Yuxin , Zhao Buhui , Qin Shangshang , Wang Yu , Guo Yong , Liu Jifeng , Xu Ting 

TITLE=A membrane-targeting magnolol derivative for the treatment of methicillin-resistant Staphylococcus aureus infections

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1385585

DOI=10.3389/fmicb.2024.1385585

ISSN=1664-302X

ABSTRACT=<p>Multidrug-resistant bacterial infections are a major global health challenge, especially the emergence and rapid spread of methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA) urgently require alternative treatment options. Our study has identified that a magnolol derivative <bold>6i</bold> as a promising agent with significant antibacterial activity against <italic>S. aureus</italic> and clinical MRSA isolates (MIC = 2–8 μg/mL), showing high membrane selectivity. Unlike traditional antibiotics, <bold>6i</bold> demonstrated rapid bactericidal efficiency and a lower propensity for inducing bacterial resistance. Compound <bold>6i</bold> also could inhibit biofilm formation and eradicate bacteria within biofilms. Mechanistic studies further revealed that <bold>6i</bold> could target bacterial cell membranes, disrupting the integrity of the cell membrane and leading to increased DNA leakage, resulting in potent antibacterial effects. Meanwhile, <bold>6i</bold> also showed good plasma stability and excellent biosafety. Notably, <bold>6i</bold> displayed good <italic>in vivo</italic> antibacterial activity in a mouse skin abscess model of MRSA-16 infection, which was comparable to the positive control vancomycin. These findings indicated that the magnolol derivative <bold>6i</bold> possessed the potential to be a novel anti-MRSA infection agent.</p>