S-Nitrosated alpha-1-acid glycoprotein exhibits antibacterial activity against multidrug-resistant bacteria strains and synergistically enhances the effect of antibiotics
S-Nitrosated alpha-1-acid glycoprotein exhibits antibacterial activity against multidrug-resistant bacteria strains and synergistically enhances the effect of antibiotics
复制标题
S-亚硝化α-1-酸性糖蛋白对多重耐药菌株表现出抗菌活性，并协同增强抗生素的作用
DOI：
10.1096/fba.1018
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发表时间：
2019
影响因子：
2.7
通讯作者：
Maruyama Toru
中科院分区：
文献类型：
--
作者：
Ishima Yu;Watanabe Kaori;Chuang Victor T. G.;Takeda Iyo;Kuroda Teruo;Ogawa Wakano;Watanabe Hiroshi;Iwao Yasunori;Ishida Tatsuhiro;Otagiri Masaki;Maruyama Toru
α-1-酸性糖蛋白(AGP)是一种主要的急性期蛋白。AGP的生物合成在炎症和感染过程中显著增加，类似于一氧化氮(NO)的生物合成。AGP变异体A(AGP)含有一个还原的半胱氨酸(Cys149)。以前，我们报道了通过与NO供体反应合成的亚硝化琼脂糖蛋白(SNO-AGP)具有很强的广谱抗菌活性(IC_(50)=10−9-10−6M)。在本研究中，使用盲肠结扎和穿孔的动物模型，我们证实了AGP在感染过程中可以内源性S-亚硝化。此外，我们还检测了SNO-AGP对多重耐药肺炎克雷伯菌和铜绿假单胞菌的抗菌活性，以探讨SNO-AGP在宿主防御系统中的作用。我们的结果表明，SNO-AGP可以抑制多药外排泵AcrAB-TolC，AcrAB-TolC是细菌多药耐药的主要贡献者。此外，SNO-AGP还降低了细菌生物膜的形成和ATP水平，表明SNO-AGP具有逆转耐药性的作用。值得注意的是，SNO-AGP与现有的抗生素(苯唑西林、亚胺培南、诺氟沙星、红霉素和四环素)显示出协同作用。综上所述，SNO-AGP参与了宿主防御系统，有可能成为单一或联合抗菌治疗的新型药物。
Alpha‐1‐acid glycoprotein (AGP) is a major acute‐phase protein. Biosynthesis of AGP increases markedly during inflammation and infection, similar to nitric oxide (NO) biosynthesis. AGP variant A (AGP) contains a reduced cysteine (Cys149). Previously, we reported thatS‐nitrosated AGP (SNO‐AGP) synthesized by reaction with a NO donor, possessed very strong broad‐spectrum antimicrobial activity (IC50= 10−9‐10−6M). In this study, using a cecal ligation and puncture animal model, we confirmed that AGP can be endogenouslyS‐nitrosated during infection. Furthermore, we examined the antibacterial property of SNO‐AGP against multidrug‐resistantKlebsiella pneumoniaeandPseudomonas aeruginosato investigate the involvement of SNO‐AGP in the host defense system. Our results showed that SNO‐AGP could inhibit multidrug efflux pump, AcrAB‐TolC, a major contributor to bacterial multidrug resistance. In addition, SNO‐AGP decreased biofilm formation and ATP level in bacteria, indicating that SNO‐AGP can revert drug resistance. It was also noteworthy that SNO‐AGP showed synergistic effects with the existing antibiotics (oxacillin, imipenem, norfloxacin, erythromycin, and tetracycline). In conclusion, SNO‐AGP participated in the host defense system and has potential as a novel agent for single or combination antimicrobial therapy.