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

Jinna Bai; Xiaoyi Zhu; Keqing Zhao; Yingjie Yan; Tao Xu; Jiaxue Wang; Jinxing Zheng; Wei Huang; Le Shi; Yongpeng Shang; Zhihui Lv; Xiaofei Wang; Yang Wu; Di Qu

doi:10.1080/22221751.2019.1595984

Emerging Microbes and Infections (Jan 2019)

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

Jinna Bai,
Xiaoyi Zhu,
Keqing Zhao,
Yingjie Yan,
Tao Xu,
Jiaxue Wang,
Jinxing Zheng,
Wei Huang,
Le Shi,
Yongpeng Shang,
Zhihui Lv,
Xiaofei Wang,
Yang Wu,
Di Qu

Affiliations

Jinna Bai: 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
Xiaoyi Zhu: 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
Keqing Zhao: Department of Otorhinolaryngology-Head and Neck Surgery, Eye & ENT Hospital, Shanghai Key Clinical Disciplines of otorhinolaryngology, Fudan University, Shanghai, People’s Republic of China
Yingjie Yan: 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
Tao Xu: Key Laboratory of Medical Molecular Virology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, People’s Republic of China
Jiaxue Wang: Department of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
Jinxing Zheng: 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
Wei Huang: Medical Clinic, Hangzhou Haiqin Sanatorium, Hangzhou, Zhejiang, People’s Republic of China
Le Shi: Department of Otorhinolaryngology-Head and Neck Surgery, Eye & ENT Hospital, Shanghai Key Clinical Disciplines of otorhinolaryngology, Fudan University, Shanghai, People’s Republic of China
Yongpeng Shang: 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
Zhihui Lv: 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
Xiaofei Wang: 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
Yang Wu: 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
Di Qu: 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

DOI: https://doi.org/10.1080/22221751.2019.1595984
Journal volume & issue: Vol. 8, no. 1
pp. 503 – 515

Abstract

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ABSTRACTMethicillin-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.

Published in Emerging Microbes and Infections

ISSN: 2222-1751 (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Infectious and parasitic diseases; Science: Microbiology
Website: https://www.tandfonline.com/journals/temi

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