ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Membrane-Targeted Schiff Base Derivatives Overcome MRSA Resistance through Phosphatidylglycerol Binding and ROS-Mediated Killing
Provisionally accepted
- The Second Hospital of Qinhuangdao, Qinhuangdao, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Sixteen N′-substituted methylene-4-chlorobenzohydrazide derivatives (C1–C16) were synthesized from commercial ethyl 4-chlorobenzoate through ester aminolysis and subsequent condensation. Of these, C1 and C16 are novel compounds, and C2–C15 are known analogues reported in the literature. Their structures were fully characterized by 1H NMR, 13C NMR, and HRMS. Preliminary in vitro antibacterial screening indicated that this series of compounds exhibited weak activity against Gram-negative bacteria but showed significant inhibitory activity against various Gram-positive bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA). Among them, compound C12 demonstrated the most potent broad-spectrum anti-Gram-positive activity (MIC = 26 μM) and selectivity. Further biological evaluation revealed that C12 displayed no significant cytotoxicity toward mammalian (VERO) cells and showed no hemolytic activity at its effective antibacterial concentrations, indicating a favorable biosafety profile. Mechanistic studies demonstrated that C12 specifically targets phosphatidylglycerol (PG) in the bacterial cell membrane, rapidly inducing membrane depolarization and increased membrane permeability. This leads to the leakage of intracellular contents (proteins, DNA) and a burst of reactive oxygen species (ROS), resulting in rapid bactericidal effects. Furthermore, C12 effectively inhibited the formation of S. aureus biofilms and exhibited a very low tendency for spontaneous resistance development. Systematic drug-likeness assessments indicated that C12 possesses moderate metabolic stability and suitable lipophilicity. In conclusion, compound C12 represents a promising anti-MRSA lead compound with potent antibacterial activity, a unique multi-mechanistic mode of action, a low risk of resistance, and a favorable safety profile, warranting further in-depth investigation.
Keywords: Anti-biofilm, antimicrobial, Druglikeness, Membrane-targeting, Schiff Bases
Received: 24 Nov 2025; Accepted: 12 Jan 2026.
Copyright: © 2026 Liu, Hu, Liu and Qu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yaguang Liu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.