In Vitro Inhibition of Growth, Biofilm Formation, and Persisters of Staphylococcus aureus by Pinaverium Bromide

Biofilm or persister cells formed by Staphylococcus aureus are closely related to pathogenicity. However, no antimicrobials exist to inhibit biofilm formation or persister cells induced by S. aureus in clinical practice. This study found that pinaverium bromide had antibacterial activity against S. aureus, with the MIC50/MIC90 at 12.5/25 μM, respectively. Pinaverium bromide (at 4 × MIC) showed a rapid bactericidal effect on S. aureus planktonic cells, and it was more effective (at least 1-log10 cfu/mL) than linezolid, vancomycin, and ampicillin at 4 h of the time-killing test. Pinaverium bromide (at 10 × MIC) significantly inhibited the formation of S. aureus persister cells (at least 3-log10 cfu/mL) than linezolid, vancomycin, and ampicillin at 24, 48, 72, 96, and 120 h of the time-killing test. Biofilm formation and adherent cells of S. aureus isolates were significantly inhibited by pinaverium bromide (at 1/2 or 1/4 × MICs). The fluorescence intensity of the membrane polarity of S. aureus increased with the treatment of pinaverium bromide (≥1 × MIC), and the MICs of pinaverium bromide increased by 4 times with the addition of cell membrane phospholipids, phosphatidyl glycerol and cardiolipin. The cell viabilities of human hepatocellular carcinoma cells HepG2 and Huh7, mouse monocyte-macrophage cells J774, and human hepatic stellate cells LX-2 were slightly inhibited by pinaverium bromide (<50 μM). There were 54 different abundance proteins detected in the pinaverium bromide-treated S. aureus isolate by proteomics analysis, of which 33 proteins increased, whereas 21 proteins decreased. The abundance of superoxide dismutase sodM and ica locus proteins icaA and icaB decreased. While the abundance of global transcriptional regulator spxA and Gamma-hemolysin component B increased. In conclusion, pinaverium bromide had an antibacterial effect on S. aureus and significantly inhibited the formation of biofilm and persister cells of S. aureus.

[1]  B. E. Castro,et al.  Multiomics characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolates with heterogeneous intermediate resistance to vancomycin (hVISA) in Latin America. , 2022, The Journal of antimicrobial chemotherapy.

[2]  Jin-xin Zheng,et al.  In vitro activities of licochalcone A against planktonic cells and biofilm of Enterococcus faecalis , 2022, Frontiers in Microbiology.

[3]  E. Mylonakis,et al.  In Vitro and In Vivo Bactericidal and Antibiofilm Efficacy of Alpha Mangostin Against Staphylococcus aureus Persister Cells , 2022, Frontiers in Cellular and Infection Microbiology.

[4]  S. Chopra,et al.  Nitazoxanide potentiates linezolid against linezolid-resistant Staphylococcus aureus in vitro and in vivo. , 2022, The Journal of antimicrobial chemotherapy.

[5]  M. L. Clodoveo,et al.  Non-Antibiotic Drug Repositioning as an Alternative Antimicrobial Approach , 2022, Antibiotics.

[6]  M. Loeb,et al.  Staphylococcus aureus bacteremia mortality: A systematic review and meta-analysis. , 2022, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[7]  P. Pelosi,et al.  Current pharmacotherapy for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia , 2021, Expert opinion on pharmacotherapy.

[8]  A. Foroushani,et al.  Antibiotic tolerance in biofilm persister cells of Staphylococcus aureus and expression of toxin-antitoxin system genes. , 2021, Microbial pathogenesis.

[9]  A. Nasser,et al.  Staphylococcus aureus: biofilm formation and strategies against it. , 2021, Current pharmaceutical biotechnology.

[10]  T. Köcher,et al.  Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis , 2021, Gastroenterology.

[11]  S. Ding,et al.  Plant Natural Flavonoids Against Multidrug Resistant Pathogens , 2021, Advanced science.

[12]  D. Qu,et al.  Diclazuril Inhibits Biofilm Formation and Hemolysis of Staphylococcus aureus. , 2021, ACS infectious diseases.

[13]  Z. Pan,et al.  Pinaverium Bromide Attenuates Lipopolysaccharide-Induced Excessive Systemic Inflammation via Inhibiting Neutrophil Priming , 2021, The Journal of Immunology.

[14]  P. Lehert,et al.  Efficacy of pinaverium bromide in the treatment of irritable bowel syndrome: a systematic review and meta-analysis , 2021, Therapeutic advances in gastroenterology.

[15]  A. Horswill,et al.  Staphylococcal Biofilm Development: Structure, Regulation, and Treatment Strategies , 2020, Microbiology and Molecular Biology Reviews.

[16]  Linying Zhou,et al.  Repurposing Antispasmodic Agent Otilonium Bromide for Treatment of Staphylococcus aureus Infections , 2020, Frontiers in Microbiology.

[17]  Rong Li,et al.  Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects. , 2019, International immunopharmacology.

[18]  M. Vestergaard,et al.  Quorum Sensing-Regulated Phenol-Soluble Modulins Limit Persister Cell Populations in Staphylococcus aureus , 2018, Front. Microbiol..

[19]  Jinzhong Xiao,et al.  Exposure to environmental microbiota explains persistent abdominal pain and irritable bowel syndrome after a major flood , 2017, Gut Pathogens.

[20]  W. Saad,et al.  Mechanism of antagonistic effects of Andrographis paniculata methanolic extract against Staphylococcus aureus. , 2017, Asian Pacific journal of tropical medicine.

[21]  L. Silver,et al.  What is an "ideal" antibiotic? Discovery challenges and path forward. , 2017, Biochemical pharmacology.

[22]  R. Fisher,et al.  Persistent bacterial infections and persister cells , 2017, Nature Reviews Microbiology.

[23]  G. Pier,et al.  A Novel Repressor of the ica Locus Discovered in Clinically Isolated Super-Biofilm-Elaborating Staphylococcus aureus , 2017, mBio.

[24]  M. Zervos,et al.  Safety and efficacy of commonly used antimicrobial agents in the treatment of enterococcal infections: a review , 2016, Expert opinion on drug safety.

[25]  D. Farrell.  Rifaximin in the Treatment of Irritable Bowel Syndrome: Is There a High Risk for Development of Antimicrobial Resistance? , 2013, Journal of clinical gastroenterology.

[26]  C. Shi,et al.  The Expression of Superoxide Dismutase (SOD) and a Putative ABC Transporter Permease Is Inversely Correlated during Biofilm Formation in Listeria monocytogenes 4b G , 2012, PloS one.

[27]  N. Heredia,et al.  Extracts of Edible and Medicinal Plants Damage Membranes of Vibrio cholerae , 2010, Applied and Environmental Microbiology.

[28]  J. O’Gara.  ica and beyond: biofilm mechanisms and regulation in Staphylococcus epidermidis and Staphylococcus aureus. , 2007, FEMS microbiology letters.

[29]  M. Valderas,et al.  Identification and Characterization of a Second Superoxide Dismutase Gene (sodM) fromStaphylococcus aureus , 2001, Journal of bacteriology.