Reversal of methicillin resistance in Staphylococcus aureus by thioridazine

Klitgaard, Janne Kudsk; Skov, Marianne Nielsine; Kallipolitis, Birgitte H.; Kolmos, Hans Jørn

doi:10.1093/jac/dkn417

Cited by 61 publications

(51 citation statements)

References 31 publications

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“…It is tempting to suggest that the similar reduction of oxacillin resistance from 256 to 2 µg/mL found in our work may be mostly due to such deactivation by phenothiazines such as chlorpromazine, in that this compound is well known to deactivate a large number of enzymes [20]. Moreover, the addition of the combinations of neurotropic drugs and β-lactam oxacillin led to lower levels of specific RNAs and proteins, indicating their interference with DNA-based processes [21]. Thioridazine also induces ultra-structural changes in MRSA such as alteration of the structure of the cell envelope, resulting in bacterial lysis at clinically relevant concentrations [3].…”

Section: Discussionsupporting

confidence: 59%

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Hadji-nejad¹,

Rahbar²,

Mehrgan³

2010

Trop. J. Pharm Res

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Purpose: To evaluate the antimicrobial and resistance-reversal activities of seven phenothiazine derivatives against one standard methicillin-sensitive and ten methicillin-resistant Staphylococcus aureus (MRSA) strains originating from human infections. Methods: Minimum inhibitory concentrations (MIC) of the compounds were determined by agar dilution method, and synergy between phenothiazines and oxacillin was investigated using Checkerboard (microbroth dilution) technique. Results: We found that all S. aureus strains, regardless of their susceptibility to oxacillin, were inhibited by phenothiazines at a concentration of 8 -256 µg/mL, with thioridazine being the most potent inhibitory agent. Phenothiazines at sub-inhibitory concentrations lowered the MIC of oxacillin from 256 to 2 µg/mL, which is a clinically significant level. The highest number of synergistic combinations, i.e., fractional inhibitory concentration (FIC) index less than 0.5, was seen with chlorpromazine and perphenazine. However, thioridazine reversed antibiotic resistance at a concentration as low as 4 µg/mL. Conclusion: Although synergy was observed at concentrations higher than those that phenothiazines usually attain in vivo, the potential offered by non-antibiotics justifies further animal experiments as well as clinical trials to establish their clinical relevance.

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Section: Discussionsupporting

confidence: 59%

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Hadji-nejad¹,

Rahbar²,

Mehrgan³

2010

Trop. J. Pharm Res

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“…We speculate that the addition of Juglans regia might interfere in the synthesis or transportation of PBP2a levels on the cell membrane. Previous studies also showed similar effects on oxacillin resistance by different compounds such as phenothiazine, chloropromazine, thioridazine, inducing physiological damage to bacterial cell membranes [39,40]. Further studies are warranted to understand the exact mechanism of action.…”

Section: Discussionmentioning

confidence: 76%

Synergistic Antimicrobial Activity of Camellia sinensis and Juglans regia against Multidrug-Resistant Bacteria

et al. 2015

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Synergistic combinations of antimicrobial agents with different mechanisms of action have been introduced as more successful strategies to combat infections involving multidrug resistant (MDR) bacteria. In this study, we investigated synergistic antimicrobial activity of Camellia sinensis and Juglans regia which are commonly used plants with different antimicrobial agents. Antimicrobial susceptibility of 350 Gram-positive and Gram-negative strains belonging to 10 different bacterial species, was tested against Camellia sinensis and Juglans regia extracts. Minimum inhibitory concentrations (MICs) were determined by agar dilution and microbroth dilution assays. Plant extracts were tested for synergistic antimicrobial activity with different antimicrobial agents by checkerboard titration, Etest/agar incorporation assays, and time kill kinetics. Extract treated and untreated bacteria were subjected to transmission electron microscopy to see the effect on bacterial cell morphology. Camellia sinensis extract showed higher antibacterial activity against MDR S. Typhi, alone and in combination with nalidixic acid, than to susceptible isolates.” We further explore anti-staphylococcal activity of Juglans regia that lead to the changes in bacterial cell morphology indicating the cell wall of Gram-positive bacteria as possible target of action. The synergistic combination of Juglans regia and oxacillin reverted oxacillin resistance of methicillin resistant Staphylococcus aureus (MRSA) strains in vitro. This study provides novel information about antimicrobial and synergistic activity of Camellia sinensis and Juglans regia against MDR pathogens

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“…Although at the time of this writing no agents are available for inhibition of type C ␤-lactamases, a variety of agents have been identified as having the potential to inhibit overexpressed efflux pumps of Gram-negative bacteria [10]. However, although some of these inhibitors of efflux pumps affect the function of the pump itself [efflux pump inhibitors (EPIs)] [11,12], there is now evidence that some EPIs may have an effect on regulatory genes involved in the control of efflux expression and genes that code for transporters [13,14]. Because of this, assessment of EPIs must also include their potential genetic actions.…”

Section: Introductionmentioning

confidence: 99%

Physiological characterisation of the efflux pump system of antibiotic-susceptible and multidrug-resistant Enterobacter aerogenes

Martins

Spengler

Martins

et al. 2010

International Journal of Antimicrobial Agents

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Enterobacter aerogenes predominates amongst Enterobacteriaceae species that are increasingly reported as producers of extended-spectrum beta-lactamases. Although this mechanism of resistance to beta-lactams is important, other mechanisms bestowing a multidrug-resistant (MDR) phenotype in this species are now well documented. Amongst these mechanisms is the overexpression of efflux pumps that extrude structurally unrelated antibiotics prior to their reaching their targets. Interestingly, although knowledge of the genetic background behind efflux pumps is rapidly advancing, few studies assess the physiological nature of the overall efflux pump system of this, or for that matter any other, bacterium. The study reported here evaluates physiologically the efflux pump system of an E. aerogenes ATCC reference as well as two strains whose MDR phenotypes are mediated by overexpressed efflux pumps. The activities of the efflux pumps in these strains are modulated by pH and glucose, although the effects of the latter are essentially restricted to pH 8, suggesting the presence of two general efflux pump systems, i.e. proton-motive force-dependent and ABC transporter types, respectively.

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Reversal of methicillin resistance in Staphylococcus aureus by thioridazine

Abstract: The present study indicates that reversal of methicillin resistance by thioridazine in MRSA may be explained by a reduced transcription of mecA and blaZ, resulting in a reduced protein level of PBP2a.

Cited by 61 publications

References 31 publications

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Synergy between phenothiazines and oxacillin against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i>

Synergistic Antimicrobial Activity of Camellia sinensis and Juglans regia against Multidrug-Resistant Bacteria

Physiological characterisation of the efflux pump system of antibiotic-susceptible and multidrug-resistant Enterobacter aerogenes

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