Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria

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.

Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors

“…Melting points (mp) were measured in a Köfler microscope (Wagner and Munz, Munich, Germany) and are uncorrected. 1 H-and 13 C-nuclear magnetic resonance (NMR) spectra were recorded at the University of Aveiro, Department of Chemistry in CDCl 3 or DMSO-d 6 (Deutero GmbH, Ely, UK) at room temperature on a Bruker Avance 300 spectrometer (300.13 MHz for 1 H and 75.47 MHz for 13 C, Bruker Biosciences Corporation, Billerica, MA, USA). Chemical shifts are expressed in δ (ppm) values relative to tetramethylsilane (TMS) as an internal reference.…”

“…The structures of the compounds were elucidated by nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), high resolution mass spectrometry (HRMS) and, in the case of compounds 13-16, X-ray crystallography. Figure S1 (Supplementary Data) presents the main 1 H and 13 C NMR chemical shifts of the signals for the newly synthesized thioxanthones 8-14.…”

“…The library of 13 thioxanthone derivatives and four tetracyclic thioxanthenes was investigated, to find their predicted binding affinities against relevant bacterial efflux pumps. Due to the effect of xanthones on strains with these transporters [13], and due to structurally related thioxanthenes reported as NorA inhibitors [18], we hypothesized that the series of in-house thioxanthones 2-7, with P-glycoprotein inhibitory activity [11], as well as the newly synthesized thioxanthones 8-18 could be effective efflux pump inhibitors. These derivatives were docked against the most relevant targets, the AcrAB-TolC efflux system from the RND family [19], and the MFS pump NorA [20], and their predicted affinity against these targets was ranked.…”

“…To investigate the potential of these compounds as efflux pump inhibitors, a preliminary screening of compounds 2-18 on two resistant Gram-positive and Gram-negative bacterial strains was performed to investigate the compounds' capability of modulating the accumulation of the efflux pump substrate ethidium bromide (EB). S. aureus 272123 is a clinical strain and was used to compare the activity of thioxanthones with xanthones which were previously tested in the same model [13]. In this strain, the expressions of the mepA and norA genes were studied in the presence of antimicrobials of natural origin, and the norA expression levels did not change [25].…”

“…Thioxanthones have also demonstrated their potential as antimicrobials and have proved to be effective in enhancing the activity of antibiotics in resistant bacterial strains [12]. They are isosteres of xanthones, which have recently been reported as bacterial efflux pump inhibitors [13]. Herein, a library of thioxanthones as potential efflux pump inhibitors was designed and synthesized, and characterized according to their antimicrobial activity, synergy with antibiotics, bacterial efflux pump inhibition and related resistance mechanisms, such as inhibition of biofilm formation and quorum-sensing.…”