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Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1&ndash, 15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure&ndash, activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 &micro, M. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.

The consequence of excessive use of macrolides is a high occurrence of mechanisms responsible for resistance to these drugs. Of 97 erythromycin-resistant bacterial strains gathered in the Wrocław area in Poland, 60% exhibited very high resistance, and those with the inducible MLSB (macrolide-lincosamide-streptogramin B) resistance phenotype predominated. Direct genetic investigation revealed that the erm genes coding for ribosomal methylases are the most frequently occurring erythromycin resistance-determining genes. No genetic resistance determinant was detected in 13% of the erythromycin-resistant strains. The efflux mechanism occurs in strains isolated from the nasopharyngeal cavity twice as often as in those isolated from other material, where the mechanism connected with target site modification predominates. Measurements of radiolabelled antibiotic accumulation inside bacterial cells revealed that in highly resistant strains (MIC > 1024 μg/ml), an important factor responsible for the resistance is the permeability barrier at the cell wall level. This would be a hitherto unknown mechanism of resistance to erythromycin in Staphylococcus aureus.