Abstract
Currently, one of the most urgent threats is antimicrobial resistance, which leads to the inefficacy of drugs in therapeutics, and can arise from several reasons, being the overexpression of efflux pumps one of them. These pumps are ubiquitous in bacteria, and their overexpression allows bacteria to develop multidrug resistance, through the extrusion of antimicrobial drugs. They can be divided into five families, being the resistance-nodulation-division (RND) family and the major facilitator superfamily (MFS) the most relevant. Efforts have been put towards a selective, efficient efflux pump inhibitor (EPI), and although some progress has been achieved, in the therapeutic scenario no EPIs have been approved.1 Our group has experience in molecular docking and synthesis of aminated thioxanthones with modulatory activity in the mammal efflux pump P-glycoprotein (P-gp), which is also useful in the detoxification of xenobiotics.2,3 Taking this into account, the aim of this work was the design of a virtual library of approximately 1.000 aminated (thio)xanthones, the performance of docking studies in bacterial efflux pumps whose crystal structure has been elucidated and available in the Protein Data Bank and in a model of the human P-gp. For the docking studies bacterial efflux pumps chosen were both from the RND family: AcrB, from the AcrAB-TolC efflux system,4 and MexB, from the MexAB-OprM efflux system.5 The compounds that will be selected for synthesis are the ones that virtually displayed good scores for the bacterial referred efflux pumps and lower scores for P-gp, since this would mean that, in vivo, these compounds would efficiently reduce antimicrobial resistance while not interfering with human detoxification pathways. Acknowledgements: This research was developed under Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds.
Highlights
RND: Resistance-nodulation-division SMR: Small multidrug resistance major facilitator superfamily (MFS): Major facilitator superfamily MATE: Multidrug and toxic compound extrusion ABC: ATP-binding cassetteMechanisms of antimicrobial resistance in a Gram-negative bacterial cell, with emphasis on efflux pumps (adapted from Allen et al Nat Rev Micro. 2010;8(4):251-9 and Durães et al Curr Med Chem. 2018) ABC transporters Ubiquitous of all systems Four conserved domains: Two transmembrane domains Two cytoplasmic domains - responsible for ATP binding Antibiotics, sugars, amino acids and vitamins are examples of substrates.Durães et al Curr Med Chem. 2018GG918, an example of an ABC inhibitorMFS transporters Largest and most extensively studied family of transporters Uniporters, symporters and antiporters Ions, carbohydrates, lipids, amino acids and nucleosides are substrates
Antimicrobial resistance can arise from several reasons, among which is the overexpression of efflux pumps
This allows bacteria to develop multidrug resistance, through the extrusion of antimicrobial drugs. They can be divided into five families, being the resistance-nodulation-division (RND) family and the major facilitator superfamily (MFS) the most relevant
Summary
Abstract: Antimicrobial resistance can arise from several reasons, among which is the overexpression of efflux pumps. Efforts have been put towards a selective, efficient efflux pump inhibitor (EPI), but no EPI has yet been introduced in the therapeutic scenario. The aim of this work was the design of a virtual library of approximately 1.000 aminated (thio)xanthones, the performance of docking studies in bacterial efflux pumps whose crystal structure has been elucidated and available, and in a model of the human P-glycoprotein (P-gp). The compounds that will be selected for synthesis are the ones that virtually displayed good scores for the bacterial referred efflux pumps and lower scores for P-gp, since this would mean that, in vivo, these compounds would efficiently reduce antimicrobial resistance while not interfering with human detoxification pathways.
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