Table_1_The study of honokiol as a natural product-based antimicrobial agent and its potential interaction with FtsZ protein.DOCX

Multidrug resistant bacteria have been a global health threat currently and frontline clinical treatments for these infections are very limited. To develop potent antibacterial agents with new bactericidal mechanisms is thus needed urgently to address this critical antibiotic resistance challenge. Natural products are a treasure of small molecules with high bioactive and low toxicity. In the present study, we demonstrated that a natural compound, honokiol, showed potent antibacterial activity against a number of Gram-positive bacteria including MRSA and VRE. Moreover, honokiol in combination with clinically used β-lactam antibiotics exhibits strong synergistic antimicrobial effects against drug-resistant S. aureus strains. Biochemical studies further reveal that honokiol may disrupt the GTPase activity, FtsZ polymerization, cell division. These biological impacts induced by honokiol may ultimately cause bacterial cell death. The in vivo antibacterial activity of honokiol against S. aureus infection was also verified with a biological model of G. mellonella larvae. The in vivo results support that honokiol is low toxic against the larvae and effectively increases the survival rate of the larvae infected with S. aureus. These findings demonstrate the potential of honokiol for further structural advancement as a new class of antibacterial agents with high potency against multidrug-resistant bacteria.

多重耐药菌目前已成为全球性公共卫生威胁，针对此类感染的一线临床治疗方案极为有限。因此，亟需开发具备全新杀菌机制的强效抗菌药物，以应对这一严峻的抗生素耐药性挑战。天然产物是一类兼具高生物活性与低毒性的小分子宝库。在本研究中，我们证实天然化合物厚朴酚（honokiol）对包括耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素肠球菌（VRE）在内的多种革兰氏阳性菌（Gram-positive bacteria）均展现出强效抗菌活性。此外，厚朴酚与临床常用的β-内酰胺类抗生素（β-lactam antibiotics）联用时，对耐药金黄色葡萄球菌（S. aureus）菌株可产生显著的协同抗菌效应。生化研究进一步揭示，厚朴酚可干扰GTP酶活性（GTPase activity）、FtsZ聚合过程以及细胞分裂环节。厚朴酚诱导的上述生物学效应最终可导致细菌细胞死亡。我们还通过大蜡螟（G. mellonella）幼虫生物模型，验证了厚朴酚抗金黄色葡萄球菌感染的体内抗菌活性。体内实验结果表明，厚朴酚对大蜡螟幼虫毒性较低，且可有效提升感染金黄色葡萄球菌的幼虫存活率。本研究结果证实，厚朴酚具备进一步结构优化的潜力，有望开发为一类针对多重耐药菌的新型强效抗菌药物。