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Antibacterial and Antibiofilm Activities of Sertindole and Its Antibacterial Mechanism against Staphylococcus aureus.

ABSTRACT: As methicillin-resistant Staphylococcus aureus has become the most prevalent antibiotic-resistant pathogen in many countries, there is an urgent demand to develop novel antibacterial agents. The purpose of this study is to investigate sertindole's antibacterial and antibiofilm properties, as well as its antibacterial mechanism against S. aureus. The MIC₅₀ and MIC₉₀ values for sertindole against S. aureus were both determined to be 50 μM, and sertindole significantly reduced S. aureus growth at a subinhibitory concentration of 1/2× MIC. Sertindole also showed remarkable potency in inhibiting the development of biofilms. Additionally, proteomic analysis revealed that sertindole could dramatically decrease the biosynthesis of amino acids and trigger the cell wall stress response and oxidative stress response. A series of tests, including membrane permeability assays, quantitative real-time reverse transcription-PCR, and electron microscope observations, revealed that sertindole disrupts cell integrity. The two-component system VraS/VraR knockout S. epidermis strain also showed enhanced sensitivity to sertindole. Overall, our data suggested that sertindole exhibited antibacterial and biofilm-inhibiting activities against S. aureus and that its antibacterial actions may involve the destruction of cell integrity.

SUBMITTER: Tang Y

PROVIDER: S-EPMC9933216 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Antibacterial and Antibiofilm Activities of Sertindole and Its Antibacterial Mechanism against Staphylococcus aureus.

Tang Yuanyuan Y Zou Fanlu F Chen Chengchun C Zhang Yiying Y Shen Zonglin Z Liu Yansong Y Deng Qiwen Q Yu Zhijian Z Wen Zewen Z

ACS omega 20230203 6

As methicillin-resistant Staphylococcus aureus has become the most prevalent antibiotic-resistant pathogen in many countries, there is an urgent demand to develop novel antibacterial agents. The purpose of this study is to investigate sertindole's antibacterial and antibiofilm properties, as well as its antibacterial mechanism against S. aureus. The MIC50 and MIC90 values for sertindole against S. aureus were both determined to be 50 μM, and sertindole ...[more]

PMID: 36816695

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Project description:BackgroundThe 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.ResultsThe 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.ConclusionLomitapide 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.

Dataset Information

Antibacterial and Antibiofilm Activities of Sertindole and Its Antibacterial Mechanism against Staphylococcus aureus.

Publications

Antibacterial and Antibiofilm Activities of Sertindole and Its Antibacterial Mechanism against <i>Staphylococcus aureus</i>.

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