Abstract
Background: Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) are frequent nosocomial pathogens for which efflux-mediated resistance and biofilm formation may contribute to the emergence of antimicrobial resistance.
Objective: Identify drugs that target efflux and biofilm formation by an in silico drug repurposing strategy and assess their efflux inhibitory and/or antibiofilm activities.
Methods: The set of all SA and SE membrane transporters and biofilm-associated proteins was used to interrogate DrugBank and generate a list of approved drugs targeting these proteins or their homologues. Seven representative candidate drugs were evaluated in an experimental model based on isogenic strains differing in the expression of the efflux pump gene norA. Each drug was tested at ¼ MIC for its ability to reduce antimicrobial MICs. Drugs with significant effect were further tested for synergism with antimicrobials by checkerboard assays and their potential to inhibit biofilm formation by the crystal violet method.
Results: We identified over 200 drugs that potentially target SA and/or SE membrane transporters or biofilm-associated proteins. Of these, we tested desipramine, chloroquine, atovaquone, topiramate, amlodipine, tariquidar and sulpiride. Tariquidar, amlodipine, desipramine and chloroquine reduced the MICs of NorA substrates in norA-overexpressing strains and presented significant synergism with NorA substrates, suggesting them as potential efflux inhibitors. Amlodipine was able to abolish biofilm formation in SA whereas desipramine and chloroquine were more effective against biofilm formation in SE.
Conclusions: Amlodipine and desipramine are new potential dual target drugs and tariquidar is a potent efflux inhibitor in staphylococci. These drugs may, in the future, be included in the fight against antimicrobial-resistant SA and SE infections.
Funding: DREBI Project Ref. 2022.07931.PTDC (FCT, Portugal)
Objective: Identify drugs that target efflux and biofilm formation by an in silico drug repurposing strategy and assess their efflux inhibitory and/or antibiofilm activities.
Methods: The set of all SA and SE membrane transporters and biofilm-associated proteins was used to interrogate DrugBank and generate a list of approved drugs targeting these proteins or their homologues. Seven representative candidate drugs were evaluated in an experimental model based on isogenic strains differing in the expression of the efflux pump gene norA. Each drug was tested at ¼ MIC for its ability to reduce antimicrobial MICs. Drugs with significant effect were further tested for synergism with antimicrobials by checkerboard assays and their potential to inhibit biofilm formation by the crystal violet method.
Results: We identified over 200 drugs that potentially target SA and/or SE membrane transporters or biofilm-associated proteins. Of these, we tested desipramine, chloroquine, atovaquone, topiramate, amlodipine, tariquidar and sulpiride. Tariquidar, amlodipine, desipramine and chloroquine reduced the MICs of NorA substrates in norA-overexpressing strains and presented significant synergism with NorA substrates, suggesting them as potential efflux inhibitors. Amlodipine was able to abolish biofilm formation in SA whereas desipramine and chloroquine were more effective against biofilm formation in SE.
Conclusions: Amlodipine and desipramine are new potential dual target drugs and tariquidar is a potent efflux inhibitor in staphylococci. These drugs may, in the future, be included in the fight against antimicrobial-resistant SA and SE infections.
Funding: DREBI Project Ref. 2022.07931.PTDC (FCT, Portugal)
| Original language | English |
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| Publication status | Published - 21 Apr 2023 |
| Event | 6º Congresso Nacional de Medicina Tropical - IHMT, Lisboa, Portugal Duration: 20 Apr 2023 → 21 Apr 2023 https://6cnmt.admeus.pt/?page=43 |
Conference
| Conference | 6º Congresso Nacional de Medicina Tropical |
|---|---|
| Abbreviated title | 6º CNMT |
| Country/Territory | Portugal |
| City | Lisboa |
| Period | 20/04/23 → 21/04/23 |
| Internet address |
