Synergistic Effects Between Thioxanthones and Oxacillin Against Methicillin-ResistantStaphylococcus aureus

Abstract

The extensive use of antimicrobials is leaving medicine with few effective therapeutic options to treat many infections due to the fact that many organisms developed resistance to commonly used drugs. It is therefore pertinent to search not only for new antimicrobials but also for compounds able to restore or potentiate the activity of existing antibiotics. We have screened a library consisting of 40 (thio)xanthone derivatives for antibacterial activity and possible synergistic effects when used in combination with antibiotics. Nine out of the 40 compounds exhibited antibacterial activity against Gram-positive bacteria. Two xanthone derivatives, 1-formyl-4-hydroxy-3-methoxy (7), 2-formyl-3-hydroxy-4-methoxyxanthone (8) and the thioxanthone derivative 1-((2-(diethylamino)ethyl)amino)-4-propoxythioxanthone (10) and its hydrochloride form 13, showed activity against a methicillin-resistant Staphylococcus aureus (MRSA) isolate with minimum inhibitory concentration (MIC) values lower than 256 μg/ml. Thioxanthone 10 demonstrated antibacterial activity and also synergy when combined with ampicillin and oxacillin against MRSA. Additionally, thioxanthone 1-(piperidin-1-yl)-4-propoxythioxanthone (9), despite not having antibacterial activity presented remarkable synergy with oxacillin against MRSA; the MIC of tioxanthone 9 and oxacillin when both were in combination were 128 and 8 μg/ml, respectively. Thioxanthones 9 and 10 were also found to be synergistic when both were combined. Subsequently, docking simulations between thioxanthones 9 and 10 and the allosteric domain of penicillin-binding protein 2A (PBP2A) were undertaken in AutoDock Vina. Both compounds had the ability to bind with an allosteric domain of PBP2A, which may explain their synergy with oxacillin. These two thioxanthone derivatives with different profiles may be promising tools for restoring the activity of oxacillin against MRSA.

Antimicrobial Activity and Phytochemical Analysis of Organic Extracts from Cleome spinosa Jaqc.

“…In addition, given the importance of the S. aureus pathogenicity and its ability to acquire resistance, new ways to combat this pathogen must be developed, among them is combination therapy using compounds that act or not on the same target. Therefore, to test the combining action became a key step in phytochemical studies (Wagner and Ulrich-Merzenich, 2009 ; Bessa et al, 2015 ; dos Santos et al, 2015 ). CL and CR extracts were able to increase the effectiveness of this antibiotic, mainly through synergistic interaction.…”

“…CL and CR extracts were able to increase the effectiveness of this antibiotic, mainly through synergistic interaction. Some plant-derived products have demonstrated the ability to reverse resistance to oxacillin (Jenkins and Cooper, 2012 ; Bessa et al, 2015 ), and the perspective is that the use of therapies based on the combination of phytochemicals and antibiotics grow in conventional medicine, as it may reduce the likelihood of dose-dependent toxicity and mutagenicity of antimicrobials (Boucher and Tam, 2006 ; Wagner and Ulrich-Merzenich, 2009 ).…”

Lichen Xanthones as Models for New Antifungal Agents

“…An initial screening of the antibacterial activity of the compounds was performed by the disk diffusion method as previously described [ 27 , 28 ]. Briefly, sterile 6 mm blank paper disks (Oxoid, Basingstoke, UK) impregnated with 15 µg of each compound were placed on MH agar plates inoculated with the bacteria.…”

“…In order to evaluate the combined effect of the compounds and clinically relevant antimicrobial drugs, a screening was conducted using the disk diffusion method, as previously described [ 27 , 28 ]. A set of antibiotic disks (Oxoid, Basingstoke, UK), to which the isolates were resistant, was selected: cefotaxime (CTX, 30 µg) for E. coli SA/2, oxacillin (OX, 1 µg) for S. aureus 66/1, and vancomycin (VA, 30 µg) for E. faecalis B3/101.…”

Bis-Indolyl Benzenoids, Hydroxypyrrolidine Derivatives and Other Constituents from Cultures of the Marine Sponge-Associated Fungus Aspergillus candidus KUFA0062

“…In order to evaluate the combined effect of the compounds and clinically relevant antimicrobial drugs, a screening was conducted using the disk diffusion method, as previously described [ 38 , 39 ]. A set of antibiotic disks (Oxoid, Basingstoke, UK) to which the isolates were resistant was selected: cefotaxime (CTX, 30 µg) for E. coli SA/2, oxacillin (OX, 1 µg) for S. aureus 66/1, and vancomycin (VA, 30 µg) for E. faecalis B3/101.…”