2. Academic Validation
  3. The role of ArlRS in regulating oxacillin susceptibility in methicillin-resistant Staphylococcus aureus indicates it is a potential target for antimicrobial resistance breakers

The role of ArlRS in regulating oxacillin susceptibility in methicillin-resistant Staphylococcus aureus indicates it is a potential target for antimicrobial resistance breakers

  • Emerg Microbes Infect. 2019;8(1):503-515. doi: 10.1080/22221751.2019.1595984.
Jinna Bai 1,  Xiaoyi Zhu 1,  Keqing Zhao 2,  Yingjie Yan 1,  Tao Xu 3,  Jiaxue Wang 4,  Jinxing Zheng 1 5,  Wei Huang 6,  Le Shi 2,  Yongpeng Shang 1,  Zhihui Lv 1,  Xiaofei Wang 1,  Yang Wu 1,  Di Qu 1
Affiliations

Affiliations

  • 1 a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences , Shanghai Medical College of Fudan University , Shanghai , People's Republic of China.
  • 2 b Department of Otorhinolaryngology-Head and Neck Surgery, Eye & ENT Hospital, Shanghai Key Clinical Disciplines of otorhinolaryngology , Fudan University , Shanghai , People's Republic of China.
  • 3 c Key Laboratory of Medical Molecular Virology , Huashan Hospital, Shanghai Medical College of Fudan University , Shanghai , People's Republic of China.
  • 4 d Department of Laboratory Medicine , Hangzhou Medical College , Hangzhou , Zhejiang , People's Republic of China.
  • 5 e Department of Infectious Diseases and the Key Laboratory of Endogenous Infection , Shenzhen Nanshan People's Hospital of Shenzhen University , Shenzhen , People's Republic of China.
  • 6 f Medical Clinic, Hangzhou Haiqin Sanatorium , Hangzhou , Zhejiang , People's Republic of China.
PMID: 30924407 DOI: 10.1080/22221751.2019.1595984
Abstract

Methicillin-resistant Staphylococcus aureus (MRSA), also known as oxacillin-resistant S. aureus, is a leading cause of community and hospital associated infections globally. In this work, we found that deletion of the arlRS two-component system genes in the USA300 and USA500 strains resulted in increased susceptibilities to oxacillin (8-16-fold decrease in minimal inhibitory concentrations). In USA300ΔarlRS, transcriptional levels of mecA or blaZ showed no obvious change, while mRNA levels of spx showed a 4-fold decrease at 4 h and a 6.3-fold decrease at 10 h. Overexpression of spx in ΔarlRS restored oxacillin resistance to a similar level in USA300. In addition, gel shift assay showed that the recombinant ArlR bound to spx promoter region. Furthermore, silencing of spx led to a significant increase of oxacillin susceptibility in multiple MRSA isolates. Our results indicate that ArlRS plays a strong role in regulating oxacillin resistance in MRSA strains, which involves direct modulation of spx expression. Moreover, oritavancin showed inhibition to ATPase activity of the recombinant histidine kinase ArlS (IC50 = 5.47 μM). Oritavancin had synergy effect on oxacillin activity against the MRSA strains in both planktonic and biofilm state. Our data suggest that ArlRS is an attractive target for breaking antimicrobial resistance of MRSA.

Keywords

ArlRS; oxacillin; two-component signal transduction system.

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