Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, Poland.
Department of Pharmaceutical Microbiology, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, Poland.
Molecules. 2020 Aug 20;25(17):3788. doi: 10.3390/molecules25173788.
Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (-) were screened for modulatory activity towards Msr(A) efflux pump present in bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure-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) 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 . The 2,4-dichlorobenzyl-hydantoin derivative was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. 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 . Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.
在此，筛选了 15 个苯哌嗪 3-苄基-5,5-二甲基海因衍生物（-），以研究它们对细菌中 Msr(A)外排泵的调节活性。进行了合成、晶体学分析、体外生物学研究和构效关系（SAR）分析。采用溴化乙锭积累测定法，在 Msr(A)外排泵过表达（K/14/1345）和缺乏（ATCC 12228）菌株中测定外排泵抑制（EPI）活性。该系列化合物还评估了降低 K/14/1345 菌株对红霉素（Msr(A)的已知底物）耐药性的能力。研究在 中确定了五个对 Msr(A)具有强调节作用的化合物。2,4-二氯苄基海因衍生物 被发现是最有效的 EPI，在 15.63µM 的低浓度下即可抑制 K/14/1345 的外排活性。晶体学支持的 SAR 分析表明，结构特性可能是活性的原因。本研究首次鉴定出能够抑制 中 Msr(A)外排泵转运体的合成化合物。因此，发现的海因衍生分子可能是一种有吸引力的抗生素佐剂组，通过 Msr(A)转运体发挥作用。
