2. Academic Validation
  3. YZ462 exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus through bacterial membrane disruption

YZ462 exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus through bacterial membrane disruption

  • BMC Microbiol. 2025 Nov 11;25(1):728. doi: 10.1186/s12866-025-04475-6.
Weikai Guo # 1 2,  Yanyang Zhao # 1,  Yuqing Yang # 1,  Wenyu Li 1,  Kexiao Wang 1,  Fang Zhou 3,  Jiaqi Li 1 3,  Xiangfeng Li 1,  Yuan Zhang 4,  Biao Hu 4,  Wenwen Zhang 3,  Xin Wei 2,  Qiming Li 5 6 7
Affiliations

Affiliations

  • 1 Henan Province EngineeringTechnology Research Center of Rapid-Accuracy Medical Diagnostics, Department of Clinical Laboratory, the First Affiliated Hospital of Henan University, Henan University, Kaifeng, 475000, China.
  • 2 The Jointed National Laboratory of Antibody Drug Engineering, the First Affiliated Hospital of Henan University, Henan University, Kaifeng, 475000, China.
  • 3 Department of Microbiology, College of Basic Medical Sciences, Henan University, Kaifeng, 475000, China.
  • 4 Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, 450000, China.
  • 5 Henan Province EngineeringTechnology Research Center of Rapid-Accuracy Medical Diagnostics, Department of Clinical Laboratory, the First Affiliated Hospital of Henan University, Henan University, Kaifeng, 475000, China. [email protected].
  • 6 The Jointed National Laboratory of Antibody Drug Engineering, the First Affiliated Hospital of Henan University, Henan University, Kaifeng, 475000, China. [email protected].
  • 7 Department of Microbiology, College of Basic Medical Sciences, Henan University, Kaifeng, 475000, China. [email protected].
  • # Contributed equally.
PMID: 41219701 DOI: 10.1186/s12866-025-04475-6
Abstract

Background: The global rise of Antibiotic resistance presents a critical public health challenge, with Staphylococcus aureus being a leading cause of hospital- and community-acquired infections. Methicillin-resistant S. aureus (MRSA) is particularly concerning due to its high prevalence, multidrug resistance, and association with severe morbidity and mortality. Developing novel small-molecule antimicrobial agents with reduced resistance susceptibility is essential to combat these infections.

Results: From our in-house compound library, we identified YZ462, a heteroaromatic-aryl scaffold compound, demonstrating potent Antibacterial activity and low toxicity. YZ462 showed strong anti-MRSA effects through Bacterial membrane disruption, increased permeability, and induction of endogenous ROS production. In vitro, it effectively killed both log-phase and stationary-phase MRSA while inhibiting biofilm formation and disrupting established biofilms. In vivo studies revealed significant reduction of Bacterial loads and improved survival rates in infected animal models. Importantly, the major S. aureus membrane component cardiolipin (CL) directly interacted with YZ462 and attenuated its Antibacterial activity, suggesting CL as a potential molecular target.

Conclusions: Our study establishes YZ462 as a promising small-molecule candidate for MRSA treatment, featuring a unique mechanism of membrane disruption and ROS induction. These results confirm its potent antimicrobial activity and demonstrate therapeutic potential against MRSA infections.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12866-025-04475-6.

Keywords

Antimicrobial agents; Bacterial infection; Gram-positive pathogen; MRSA; YZ462.

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