In vitro/vivo Mechanism of Action of MP1102 With Low/Nonresistance Against Streptococcus suis Type 2 Strain CVCC 3928
In vitro/vivo Mechanism of Action of MP1102 With Low/Nonresistance Against Streptococcus suis Type 2 Strain CVCC 3928
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DOI：
10.3389/fcimb.2019.00048
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发表时间：
2019-02
影响因子：
5.7
通讯作者：
Fei Zhao;Na Yang;Xiumin Wang;R. Mao;Ya Hao;Zhanzhan Li;Xiao Wang;D. Teng;H. Fan;Jianhua Wang
中科院分区：
文献类型：
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作者：
Fei Zhao;Na Yang;Xiumin Wang;R. Mao;Ya Hao;Zhanzhan Li;Xiao Wang;D. Teng;H. Fan;Jianhua Wang
链球菌病被认为是养猪业的主要传染病。猪链球菌2型被认为是致病力最强的菌种，严重威胁人和猪的健康，造成严重的经济损失。在这项研究中，多个在体外和体内的作用，MP 1102对多药耐药S。首次对猪流感进行了研究。MP 1102对S.猪的最低抑菌浓度（MIC = 0.028-0.228 μM），杀菌迅速，抗生素后效应比头孢曲松长，与林可霉素、青霉素和头孢曲松有协同或相加作用（FICI = 0.29-0.96）。连续传30代后未出现抗性突变体。在MP 1102的存在下。流式细胞仪分析和电镜观察表明，MP 1102对S. suis细胞膜完整性和受影响的S. suis细胞超微结构和膜形态。具体而言，观察到明显起皱的表面、细胞内内容物渗漏和细胞溶解，建立了对该病原体不耐药的细胞基础。DNA凝胶阻滞和圆二色性分析表明，MP 1102与DNA发生相互作用，改变了DNA的构象，甚至导致螺旋结构消失。这一结果进一步支持了通过与细胞内靶点相互作用的非耐药性的机制基础，这可能是MP 1102跨膜转运后继发性损伤的一种手段。经2.5-5.0 mg/kg MP 1102处理后，用S. SUIS为83.3- 100%。MP 1102可减少肝、肺、脾和血液中细菌移位，抑制IL-1β和TNF-α的释放，减轻S.猪。这些结果表明，MP 1102是一种有效的新型抗菌剂，用于治疗猪链球菌病。
Streptococcosis is recognized as a leading infectious disease in the swine industry. Streptococcus suis serotype 2 is regarded as the most virulent species, which threatens human and pig health and causes serious economic losses. In this study, multiple in vitro and in vivo effects of MP1102 on multidrug resistant S. suis was studied for the first time. MP1102 exhibited significant antibacterial activity against S. suis (minimum inhibitory concentration, MIC = 0.028–0.228 μM), rapid bacteriocidal action, a longer postantibiotic effect than ceftriaxone, and a synergistic or additive effect with lincomycin, penicillin, and ceftriaxone (FICI = 0.29–0.96). No resistant mutants appeared after 30 serial passages of S. suis in the presence of MP1102. Flow cytometric analysis and electron microscopy observations showed that MP1102 destroyed S. suis cell membrane integrity and affected S. suis cell ultrastructure and membrane morphology. Specifically, a significantly wrinkled surface, intracellular content leakage, and cell lysis were noted, establishing a cyto-basis of nonresistance to this pathogen. DNA gel retardation and circular dichroism analysis indicated that MP1102 interacted with DNA by binding to DNA and changing the DNA conformation, even leading to the disappearance of the helical structure. This result further supported the mechanistic basis of nonresistance via interaction with an intracellular target, which could serve as a means of secondary injury after MP1102 is transported across the membrane. Upon treatment with 2.5–5.0 mg/kg MP1102, the survival of mice challenged with S. suis was 83.3–100%. MP1102 decreased bacterial translocation in liver, lung, spleen, and blood; inhibited the release of interleukin-1β and tumor necrosis factor-α; and relieved the lung, liver, and spleen from acute injury induced by S. suis. These results suggest that MP1102 is a potent novel antibacterial agent for the treatment of porcine streptococcal disease.