Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections
Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections
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氟苯烷基取代的氰基胍衍生物作为细菌选择性 MATE 转运蛋白抑制剂用于治疗抗生素耐药性感染
DOI：
10.1016/j.bmc.2022.117042
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发表时间：
2022
影响因子：
3.5
通讯作者：
Masaaki Omote
中科院分区：
文献类型：
--
作者：
Susumu Shinya;Kentaro Kawai;Naoki Kobayashi;Yukiko Karuo;Atsushi Tarui;Kazuyuki Sato;Masato Otsuka;Masaaki Omote
多药和毒素挤出（MATE）转运体家族成员多药耐药蛋白HmrM的药物外排泵抑制剂，旨在提高多药耐药菌的药物敏感性，恢复氟喹诺酮类药物（如诺氟沙星）的抗菌效果。该先导抑制剂由已知hMATE1抑制剂西咪替丁制备，在人体细胞中，在非细胞毒浓度下，表达hmrm的菌株对诺氟沙星的耐药性降低了92%，表达多药耐药蛋白mdtk的菌株对诺氟沙星的耐药性降低了86%。这些结果表明，该抑制剂是开发具有新的作用机制的药物的主要候选者，这些药物可以与抗菌药物协同作用，对抗多药耐药细菌引起的感染。
Drug efflux pump inhibitors for the multidrug resistance protein HmrM, a member of the multidrug and toxin extrusion (MATE) family of transporters, were investigated to increase the drug susceptibility of multidrug-resistant bacteria and restore the antimicrobial effect of fluoroquinolones, such as norfloxacin. The lead inhibitor, prepared from the known hMATE1 inhibitor cimetidine, reduced the norfloxacin resistance of HmrM-expressing strains by 92% at non-cytotoxic concentrations in human cells, and multidrug resistance protein MdtK-expressing strains by 86%. These results indicated that the inhibitor is a lead candidate for the development of drugs with a novel mechanism of action against infections caused by multidrug-resistant bacteria that act synergistically with antimicrobial drugs.