Discovery of membrane-targeting amphiphilic honokiol derivatives containing an oxazolethione moiety to combat methicillin-resistant Staphylococcus aureus (MRSA) infections.

Autor: Yang R; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China., Cui L; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China., Xu T; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China., Zhong Y; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China., Hu S; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China., Liu J; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China., Qin S; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China., Wang X; Department of Dermatology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China. Electronic address: wxl-513@163.com., Guo Y; Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China. Electronic address: guoyong_122@163.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 05; Vol. 279, pp. 116868. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1016/j.ejmech.2024.116868
Abstrakt: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major pathogen causing infections in hospitals and the community, and there is an urgent need for the development of novel antibacterials to combat MRSA infections. Herein, a series of amphiphilic honokiol derivatives containing an oxazolethione moiety were prepared and evaluated for their in vitro antibacterial and hemolytic activities. The screened optimal derivative, I3, exhibited potent in vitro antibacterial activity against S. aureus and clinical MRSA isolates with MIC values of 2-4 μg/mL, which was superior to vancomycin in terms of its rapid bactericidal properties and was less susceptible to the development of resistance. The SARs analysis indicated that amphiphilic honokiol derivatives with fluorine substituents had better antibacterial activity than those with chlorine and bromine substituents. In vitro and in vivo toxicity studies revealed that I3 has relatively low toxicity. In a MRSA-infected mouse skin abscess model, I3 (5 mg/kg) effectively killed MRSA at the infected site and attenuated the inflammation effects, comparable to vancomycin. In a MRSA-infected mouse sepsis model, I3 (12 mg/kg) was found to significantly reduce the bacterial load in infected mice and increase survival of infected mice. Mechanistic studies indicated that I3 has membrane targeting properties and can interact with phosphatidylglycerol (PG) and cardiolipin (CL) of MRSA cell membranes, thereby disrupting MRSA cell membranes, further inducing the increase of reactive oxygen species (ROS), protein and DNA leakage to achieve rapid bactericidal effects. Finally, we hope that I3 is a potential candidate molecule for the development of antibiotics to conquer superbacteria-related infections.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: