Abstract
The emergence of multidrug and extensively drug-resistant pathogenic bacteria able to resist to the action of a wide range of antibiotics is becoming a growing problem for public health. The search for new compounds with the potential to help in the reversion of bacterial resistance plays an important role in current medicinal chemistry research. Under this scope, bacterial efflux pumps are responsible for the efflux of antimicrobials, and their inhibition could reverse resistance. In this study, the multidrug resistance reversing activity of a series of xanthones was investigated. Firstly, docking studies were performed in the AcrAB-TolC efflux pump and in a homology model of the NorA pump. Then, the effects of twenty xanthone derivatives on bacterial growth were evaluated in Staphylococcus aureus 272123 and in the acrA gene-inactivated mutant Salmonella enterica serovar Typhimurium SL1344 (SE03). Their efflux pump inhibitory properties were assessed using real-time fluorimetry. Assays concerning the activity of these compounds towards the inhibition of biofilm formation and quorum sensing have also been performed. Results showed that a halogenated phenylmethanamine xanthone derivative displayed an interesting profile, as far as efflux pump inhibition and biofilm formation were concerned. To the best of our knowledge, this is the first report of xanthones as potential efflux pump inhibitors.
Highlights
Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leixões, Av
Various efflux pump-related aspects of bacterial resistance have been investigated. Since it is the first report on xanthones as potential EPIs, the general activity of the compounds and the interplay with different virulence and resistance determinants were investigated
The results disclosed the potential of xanthone derivatives to circumvent antimicrobial resistance mechanisms
Summary
The search for new compounds with the potential to help in the reversion of bacterial resistance plays an important role in current medicinal chemistry research Under this scope, bacterial efflux pumps are responsible for the efflux of antimicrobials, and their inhibition could reverse resistance. Multiple antibiotic resistance can arise through a series of distinct molecular mechanisms by different ways: modification of the antibiotic molecule, mutations, modifications and protection of the target, and the prevention of the access of the drug to the target One example of the latter mechanism is an increase in the efflux of antimicrobials, which can happen through the overexpression of efflux pumps present in the bacterial membrane and lead to multidrug resistance [2]
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