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.

Scheme 1

Synthesis of alkyl-, acetyl-, and nitro-coumarin derivatives. Reagents and conditions: (a) acetic anhydride, pyridine, rt, ultrasound irradiation; (b) allyl bromide, geranyl bromide, or prenyl bromide, K₂CO₃, acetonitrile, and reflux; (c) HNO₃/AcOH, 0–5°C for 30 min and then 90 min at rt.

Figure 1

Representation of the PSA (Polar Surface Area) of active (13 and 16) and inactive (2 and 22) compounds using VEJA ZZ program. White represents polar surface and grey-dark represents no-polar surfaces.

Figure 2

Interactions observed in the compound 18-PBP complex.