2. Academic Validation
  3. Antibacterial activities and action mode of anti-hyperlipidemic lomitapide against Staphylococcus aureus

Antibacterial activities and action mode of anti-hyperlipidemic lomitapide against Staphylococcus aureus

  • BMC Microbiol. 2022 Apr 26;22(1):114. doi: 10.1186/s12866-022-02535-9.
Yufang Zhang  # 1 2 3,  Yiying Zhang  # 1 2,  Chengchun Chen  # 1 2,  Hang Cheng 1 2,  Xiangbin Deng 1 2,  Duoyun Li 1 2,  Bing Bai 1 2,  Zhijian Yu 1 2,  Qiwen Deng 4 5,  Jie Guo 6 7,  Zewen Wen 8 9
Affiliations

Affiliations

  • 1 Department of Infectious Diseases and Shenzhen Key Lab of Endogenous Infection, Shenzhen Nanshan People's Hospital and the 6th affiliated Hospital of Guangdong Medical University, Shenzhen, 518052, China.
  • 2 Quality Control Center of Hospital Infection Management of Shenzhen, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China.
  • 3 Class of Biological Science, Futian District, Shenzhen College of International Education, No. 3 Antuoshan 6th Rd, Shenzhen, 518040, China.
  • 4 Department of Infectious Diseases and Shenzhen Key Lab of Endogenous Infection, Shenzhen Nanshan People's Hospital and the 6th affiliated Hospital of Guangdong Medical University, Shenzhen, 518052, China. qiwendeng@hotmail.com.
  • 5 Quality Control Center of Hospital Infection Management of Shenzhen, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China. qiwendeng@hotmail.com.
  • 6 Department of Infectious Diseases and Shenzhen Key Lab of Endogenous Infection, Shenzhen Nanshan People's Hospital and the 6th affiliated Hospital of Guangdong Medical University, Shenzhen, 518052, China. 15699204528@163.com.
  • 7 Quality Control Center of Hospital Infection Management of Shenzhen, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China. 15699204528@163.com.
  • 8 Department of Infectious Diseases and Shenzhen Key Lab of Endogenous Infection, Shenzhen Nanshan People's Hospital and the 6th affiliated Hospital of Guangdong Medical University, Shenzhen, 518052, China. wenzw05@163.com.
  • 9 Quality Control Center of Hospital Infection Management of Shenzhen, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China. wenzw05@163.com.
  • # Contributed equally.
PMID: 35473561 DOI: 10.1186/s12866-022-02535-9
Abstract

Background: The increasing emergence of multidrug-resistant Gram-positive Bacterial infections necessitates new Antibacterial agents with novel mechanisms of action that can be used to treat these infections. Lomitapide has been approved by FDA for years in reducing levels of low-density lipoprotein (LDL) in cases of familial hypercholesterolemia, whereas the Antibacterial effect of lomitapide remains elusive. In this study, the inhibitory activities of lomitapide against Gram-positive bacteria were the first time explored. Quantitative proteomics analysis was then applied to investigate the mechanisms of action of lomitapide.

Results: The minimum inhibitory concentration (MIC) values of lomitapide against Gram-positive bacteria including both methicillin sensitive and resistant Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Streptococcus agalactiae were range 12.5-50 μM. Moreover, lomitapide also inhibited anti-biofilm activity against clinical S. aureus isolates. A total of 106 proteins with > 1.5-fold changes in expression were identified upon 1/2 × MIC lomitapide exposure, including 83 up-regulated proteins and 23 down-regulated proteins. Based on bioinformatics analysis, the expression of cell wall damage response proteins including two-component system VraS/VraR, lipoteichoic acid (LPA) D-alanylnation related proteins D-alanyl carrier protein (dltC) and carrier protein Ligase (dltA), methionine sulfoxide reductases (mrsA1 and mrsB) were up-regulated. Moreover, the expression of SaeS and multiple fibrinogen-binding proteins (SAOUHSC_01110, FnBPB, SAOUHSC_02802, SdrC, SdrD) which were involved in the Bacterial adhesion and biofilm formation, was inhibited by lomitapide. Furthermore, VraS/VraR deletion mutant (ΔvraSR) showed an enhanced lomitapide sensitivity phenotype.

Conclusion: Lomitapide displayed broad antimicrobial activities against Gram-positive bacteria. The Antibacterial effect of lomitapide may be caused by cell wall destruction, while the anti-biofilm activity may be related to the inhibition of surface proteins.

Keywords

Biofilm formation; Lomitapide; Quantitative proteomics; S. aureus.

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