scholarly journals Clinically Approved Drugs Inhibit the Staphylococcus aureus Multidrug NorA Efflux Pump and Reduce Biofilm Formation

2019 ◽  
Vol 10 ◽  
Author(s):  
Saskia Zimmermann ◽  
Mareike Klinger-Strobel ◽  
Jürgen A. Bohnert ◽  
Sindy Wendler ◽  
Jürgen Rödel ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Approved Drugs

scholarly journals Repurposing Approved Drugs as Fluoroquinolone Potentiators to Overcome Efflux Pump Resistance in Staphylococcus aureus

2021 ◽  
Author(s):  
Nisha Mahey ◽  
Rushikesh Tambat ◽  
Nishtha Chandal ◽  
Dipesh Kumar Verma ◽  
Krishan Gopal Thakur ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Nosocomial Infections ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Drug Efflux ◽  
Content Type ◽  
Approved Drugs

Staphylococcus aureus is a frequent pathogen bacterium and the predominant cause of worsened nosocomial infections. Efflux pumps contribute to drug efflux and are reportedly associated with biofilm formation, thereby promoting difficult-to-treat biofilm-associated S. aureus infections.

scholarly journals Antifungal Azoles as Tetracycline Resistance-Modifiers in Staphylococcus aureus

2021 ◽  
Author(s):  
Nisha Mahey ◽  
Rushikesh Tambat ◽  
Dipesh Kumar Verma ◽  
Nishtha Chandal ◽  
Krishan Gopal Thakur ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Silico ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Efflux Pump Inhibitors ◽  
Approved Drugs ◽  
Major Facilitator

Staphylococcus aureus has developed resistance to antimicrobials since its first use. The S. aureus major facilitator superfamily (MFS) efflux pump Tet(K) contributes to resistance to tetracyclines. The efflux pump diminishes antibiotic accumulation, and biofilm hampers the diffusion of antibiotics. None of the currently known compounds have been approved as efflux pump inhibitors (EPIs) for clinical use. In the current study, we screened clinically approved drugs for possible Tet(K) efflux pump inhibition. In silico docking followed by in vitro checkerboard assays, we identified five azoles (the fungal ergosterol synthesis inhibitors) showing the putative EPI-like potential with a fractional inhibitory concentration index of ≤0.5, indicating synergism. The functionality of the azoles was confirmed using ethidium bromide (EtBr) accumulation and efflux inhibition assays. In time-kill kinetics, the combination treatment with butoconazole engendered a marked increase in the bactericidal capacity of tetracycline. When assessing the off-target effects of the azoles, we observed no disruption of bacterial membrane permeability and polarization. Finally, the combination of azoles with tetracycline led to a significant eradication of preformed mature biofilms. This study is the primary representation of azoles that can be repurposed as putative Tet(K) EPIs and to reduce biofilm formation at clinically relevant concentrations. IMPORTANCE Staphylococcus aureus use efflux pumps to transport antibiotics out of the cell and thus increase the dosage at which they endure antibiotics. Also, efflux pumps play a role in biofilm formation by the excretion of extracellular matrix molecules. One way to combat these pathogens may be to reduce the activity of efflux pumps and thereby increase pathogen sensitivity to existing antibiotics. We describe the in silico-based screen of clinically approved drugs that identified antifungal azoles inhibiting Tet(K); a pump belongs to the Major Facilitator Superfamily and shows that these compounds bind to and block the activity of the Tet(K) pump. Azoles enhanced the susceptibility of tetracycline against S. aureus and its methicillin-resistant strains. The combination of azoles with tetracycline led to a significant reduction in preformed biofilms. Repurposing of approved drugs may help solve the classical toxicity issues related to efflux pump inhibitors.

scholarly journals A novel mechanism of action of ketoconazole: inhibition of the NorA efflux pump system and biofilm formation in multidrug-resistant Staphylococcus aureus

2019 ◽  
Vol Volume 12 ◽  
pp. 1703-1718 ◽  
Author(s):  
Rehab M Abd El-Baky ◽  
Tim Sandle ◽  
James John ◽  
Gamal El-Din AA Abuo-Rahma ◽  
Helal F Hetta
Keyword(s):  
Staphylococcus Aureus ◽  
Mechanism Of Action ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Pump System

scholarly journals MgrA Represses Biofilm Formation in Staphylococcus aureus

2008 ◽  
Vol 76 (12) ◽  
pp. 5645-5654 ◽  
Author(s):  
María Pilar Trotonda ◽  
Sandeep Tamber ◽  
Guido Memmi ◽  
Ambrose L. Cheung
Keyword(s):  
Staphylococcus Aureus ◽  
Genetic Analysis ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Genetic Locus ◽  
Surface Proteins ◽  
Extracellular Dna ◽  
Crucial Component ◽  
Pump Activity ◽  
Pleiotropic Regulator

ABSTRACT MgrA is a pleiotropic regulator that controls autolysis, virulence, and efflux pump activity in Staphylococcus aureus. We recently found that mgrA mutants of strains RN6390, SH1000, and MW2 also displayed enhanced biofilm formation compared with their respective parents. The biofilms formed by mgrA mutants of RN6390 and MW2 are independent of sigB and ica loci, two genetic elements that have been previously associated with biofilm formation in S. aureus. Biofilms formed by mgrA mutants are dependent on the expression of surface proteins mediated by the sortase gene srtA. Extracellular DNA was also a crucial component of the early biofilm of mgrA mutants. Genetic analysis indicated that biofilm formation in mgrA mutants is mediated in part by agr RNAIII, a genetic locus regulated by mgrA. Additionally, SarA is important to biofilm formation in mgrA mutants since the double sarA mgrA mutants failed to form biofilms compared to single mgrA mutants of RN6390 and MW2. However, the SarA-mediated effect is independent of agr and proteases such as V8 protease and aureolysin. Collectively, our data showed MgrA to be a repressor of biofilm formation, and biofilms formed by mgrA mutants have features that are distinct from other reported biofilm types in S. aureus.

Synthesis of new Enrofloxacin Derivatives as Potential Antibiofilm Drugs Against Staphylococcus Aureus and Klebsiella Pneumoniae

2020 ◽  
Vol 17 (1) ◽  
pp. 85-96
Author(s):  
Hina Siddiqui ◽  
Haroon M. Haniffa ◽  
Ayaz Ahmed ◽  
Muhammad I. Choudhary
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Aromatic Amines ◽  
Normal Cell ◽  
Mouse Fibroblast ◽  
Food Industries ◽  
Control Drug ◽  
Bactericidal Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: The antimicrobial resistance due to biofilm formation among bacteria is a significant problem in the healthcare and food industries. Objective: The current study describes the synthesis of enrofloxacin derivatives 2-17, and the evaluation of their anti-bacterial and anti-biofilm activities. Methods: Compounds 2-17 were synthesized through the acylation of enrofloxacin with thionyl chloride, followed by reaction with different aromatic amines. The new analogues identified among the sixteen compounds were 2-7, 11, 14, and 17. Results: Compound 2 appeared to be effective against pathogens S. aureus as well as K. pneumonia, whereas, compound 11 was found active against K. pneumonia only. Compound 2 inhibited >75% biofilm formation of S. aureus at 20 μg/mL and K. pneumonia at 10 μg/mL concentrations. These doses are far below the bactericidal concentration of compound 2, suggesting the anti-virulence mechanism of these compounds. Compound 11 inhibited 60% biofilm formation of K. pneumoniae at 70 μg/mL concentration. Compound 5 inhibited the biofilm of K. pneumoniae at 62 μg/mL concentration but also had bactericidal properties at this concentration. Interestingly, compound 2 eradicated the preformed biofilm of both the pathogens at much lower doses as compared to control drug, gentamycin and substrate, enrofloxacin. Cytotoxicity of compounds 2–17 was checked by a standard method using 3T3 normal cell lines (mouse fibroblast), all compounds were found to be noncytotoxic. Conclusion: These compounds can be used alone or with FDA approved drugs to overcome biofilm related K. pneumoniae and S. aureus infections.

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