title: Modulation of Drug Resistance in Staphylococcus aureus with Coumarin Derivatives.
abstract: Semisynthetic and commercial coumarins were investigated for their antibacterial and adjuvant properties with antibiotic agents against norfloxacin, erythromycin, and tetracycline resistant Staphylococcus aureus as based on efflux mechanisms. The coumarins and certain commercial antibiotics had their Minimum Inhibitory Concentrations determined by broth microdilution assay against resistant S. aureus strains which overexpress efflux pump proteins. For evaluation of the modulatory activity, the antibiotics MICs were determined in the presence of the coumarin derivatives at subinhibitory concentration. Although the coumarins did not display relevant antibacterial activity (MIC ≥ 128 µg/mL), they did modulate the antibiotics activities. Various coumarins, especially the alkylated derivatives in combination with antibiotics at subinhibitory concentrations, modulated antibiotic activity, reducing the MIC for tetracycline and norfloxacin by 2 to 8 times. Polar Surface Area (PSA) studies were performed and the fact that the presence of apolar groups is an important factor for the modulatory activity of coumarins was corroborated. Docking on the Penicillin-Binding Protein from MRSA identified that 18 is a potential ligand presenting low E binding. The results indicate that coumarin derivatives modulated antibiotic resistance and may be used as potential antibiotic adjuvants, acting by bacterial efflux pump inhibition in S. aureus.
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: Rodrigo Santos Aquino
authors.initials: RS
authors.lastname: de Araújo
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: José Maria
authors.initials: JM
authors.lastname: Barbosa-Filho
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: Marcus Tullius
authors.initials: MT
authors.lastname: Scotti
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Scotti
authors.affiliation: Laboratory of Genetics of Microorganisms, Molecular Biology Department, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: Ryldene Marques Duarte
authors.initials: RM
authors.lastname: da Cruz
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil; Laboratory of Genetics of Microorganisms, Molecular Biology Department, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: Vivyanne Dos Santos
authors.initials: Vdos S
authors.lastname: Falcão-Silva
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil; Laboratory of Genetics of Microorganisms, Molecular Biology Department, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil.
authors.forename: José Pinto
authors.initials: JP
authors.lastname: de Siqueira-Júnior
authors.affiliation: Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, 58051-900 João Pessoa, PB, Brazil; Laboratory of Synthesis and Drug Delivery, Biological Science Department, State University of Paraíba, 58071-160 João Pessoa, PB, Brazil.
authors.forename: Francisco Jaime Bezerra
authors.initials: FJ
authors.lastname: Mendonça-Junior