Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro
Introduction
Efflux pumps that are an integral part of the bacterial plasma membrane have been shown during the past decade to account for much of the resistance of bacteria to one or more antibiotics [1]. Consequently, much attention has been focused on the development of drugs that specifically inhibit the activity of efflux pumps that bestow antibiotic resistance [2]. In this manner, such compounds could be used as adjuncts to antibiotics for which resistance is noted. An obvious limitation of this approach is that resistance to antibiotics such as beta-lactams, whose antibiotic activity resides in the inhibition of penicillin binding proteins (PBPs) responsible for the synthesis of the bacterial cell wall [3], is not expected to be the result of an efflux pump inasmuch as direct access to these PBPs would not be prevented by the action of the pump. Chlorpromazine has been reported to render penicillin resistant (non-beta-lactamase producers) as susceptible to penicillin as any other penicillin sensitive strain [4]. Because chlorpromazine as well as other phenothiazines has been shown to inhibit influx and energy dependent efflux pumps [5], [6] and has also been shown to cause (cure) the elimination of plasmids from infected bacteria [7], the question of whether chlorpromazine promotes reduction of resistance to a beta-lactam by directly affecting an efflux pump or by the elimination of plasmids that code for the efflux pumps that employ the beta-lactam as a substrate, must be answered. This study attempted to determine whether a phenothiazine alters the susceptibility of methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus strains to oxacillin.
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Materials
Chlorpromazine (CPZ), thioridazine (TZ), oxacillin (OXA), reserpine and verapamil were purchased from Sigma Aldrich Quimica SA. (Madrid, Spain). Trypticase soy broth (TSB) and trypticase soy agar (TSA) were purchased from Difco (Detroit, MI). All solutions of phenothiazines were prepared in sterile, distilled water on the day of the experiment.
Bacterial strains
S. aureus strains employed in this study are the ATCC 25923 that is to serve as the control and clinical strains of methicillin (oxacillin) susceptible
Results
The MICs and MBCs of oxacillin, and general inhibitors of efflux pumps CPZ, TZ, reserpine and verapamil against MSSA and MRSA strains is summarised in Table 1. Oxacillin inhibits the control strain and two other clinical MSSA strains at similar concentrations (MIC 0.2 to 0.3 mg/l). Killing of MSSA and MRSA strains by oxacillin was not observed with the concentrations as high as 300 and 500 mg/l, respectively (data not shown). CPZ and TZ inhibited the growth of MSSA and MRSA strains, with TZ
Discussions
The results presented in this study showed clearly that susceptibility to oxacillin is significantly affected by CPZ or TZ with MRSA strains only. The reduction of oxacillin resistance from >500 to 100 mg/l was consistent with either 1/2 MIC of CPZ or TZ. The resistance of one particular strain (MRSA 4) was significantly more affected by these phenothiazines. Even with this strain, complete reversal of resistance to oxacillin could not be achieved at concentrations of the phenothiazines that by
Acknowledgements
We wish to thank the members of the COST ACTION B16 of the European Commission for their valuable suggestions and to the Scientific Committee of the Institute of Hygiene of Lisbon, Portugal, for its support and advice. This work was supported by grant no. 37579/FCB/2001 from the Portuguese Fundação para a Ciência e Tecnologia (FCT).
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