title: Synergistic Effects Between Thioxanthones and Oxacillin Against Methicillin-Resistant Staphylococcus 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.
authors: 1 Laboratório de Microbiologia e Tecnologia Alimentar, Departamento de Produção Aquática, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto , Porto, Portugal .|2 Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto , Porto, Portugal .
authors: Lucinda J
authors: LJ
authors: Bessa
authors: 3 Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Universidade do Porto , Porto, Portugal .
authors: Andreia
authors: A
authors: Palmeira
authors: 3 Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Universidade do Porto , Porto, Portugal .
authors: Ana S
authors: AS
authors: Gomes
authors: 2 Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto , Porto, Portugal .|4 Departamento de Biologia, Faculdade de Ciências, Universidade do Porto , Porto, Portugal .
authors: Vitor
authors: V
authors: Vasconcelos
authors: 2 Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto , Porto, Portugal .|3 Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Universidade do Porto , Porto, Portugal .
authors: Emília
authors: E
authors: Sousa
authors: 2 Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto , Porto, Portugal .|3 Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Universidade do Porto , Porto, Portugal .
authors: Madalena
authors: M
authors: Pinto
authors: 1 Laboratório de Microbiologia e Tecnologia Alimentar, Departamento de Produção Aquática, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto , Porto, Portugal .|2 Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto , Porto, Portugal .
authors: Paulo
authors: P
authors: Martins da Costa
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001426:Bacterial Proteins / Q000378:metabolism; D004357:Drug Synergism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010068:Oxacillin / Q000494:pharmacology*; D046915:Penicillin-Binding Proteins / Q000378:metabolism; D013892:Thioxanthenes / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D013892:Thioxanthenes; D044004:Xanthones; C487789:mecA protein, Staphylococcus aureus; D000667:Ampicillin; C484911:thioxanthone; D010068:Oxacillin