Novel small molecules that increase the susceptibility of Neisseria gonorrhoeae to cationic antimicrobial peptides by inhibiting lipid A phosphoethanolamine transferase.
Novel small molecules that increase the susceptibility of Neisseria gonorrhoeae to cationic antimicrobial peptides by inhibiting lipid A phosphoethanolamine transferase.
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DOI：
10.1093/jac/dkac204
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发表时间：
2022-08-25
影响因子：
5.2
通讯作者：
Kahler, Charlene M.
中科院分区：
文献类型：
--
作者：
Mullally, Christopher;Stubbs, Keith A.;Thai, Van C.;Anandan, Anandhi;Bartley, Stephanie;Scanlon, Martin J.;Jarvis, Gary A.;John, Constance M.;Lim, Katherine Y. L.;Sullivan, Courtney M.;Sarkar-Tyson, Mitali;Vrielink, Alice;Kahler, Charlene M.
淋病奈瑟菌是一种专门的人类病原体，通常感染泌尿生殖道导致淋病。用抗生素经验性治疗淋病已导致多药耐药，需要新的治疗方法。脂寡糖磷酸乙醇胺转移酶A （EptA）的失活导致感染模型中病原体的衰减。EptA能将磷酸乙醇胺附着在脂质A上。预测抑制EptA的小分子可以通过人类先天免疫反应增强对淋球菌的自然清除。研究了一个小片段化合物文库对淋病奈瑟菌FA1090对多粘菌素b敏感性的增强作用，以及这些化合物对脂质A合成和感染模型生存能力的影响。3个化合物135、136和137使菌株FA1090对多粘菌素B的敏感性提高了4倍。用这三种化合物预处理细菌细胞可增强巨噬细胞的杀伤作用。MALDI-TOF质谱分析显示，暴露于化合物137的细菌细胞中，只有脂质A被磷酸乙醇胺修饰的水平降低了17%，THP-1细胞的细胞因子反应刺激减少。通过1D饱和转移差核磁共振测定，137对纯化EptA的亲和力高于起始材料。治疗8株耐多药菌株，其中137株对多粘菌素B的敏感性增加。小分子已被设计与EptA结合，抑制磷酸乙醇胺对脂质A的添加，并能使淋病奈瑟菌对巨噬细胞的杀伤敏感。
Neisseria gonorrhoeae is an exclusively human pathogen that commonly infects the urogenital tract resulting in gonorrhoea. Empirical treatment of gonorrhoea with antibiotics has led to multidrug resistance and the need for new therapeutics. Inactivation of lipooligosaccharide phosphoethanolamine transferase A (EptA), which attaches phosphoethanolamine to lipid A, results in attenuation of the pathogen in infection models. Small molecules that inhibit EptA are predicted to enhance natural clearance of gonococci via the human innate immune response. A library of small-fragment compounds was tested for the ability to enhance susceptibility of the reference strain N. gonorrhoeae FA1090 to polymyxin B. The effect of these compounds on lipid A synthesis and viability in models of infection were tested. Three compounds, 135, 136 and 137, enhanced susceptibility of strain FA1090 to polymyxin B by 4-fold. Pre-treatment of bacterial cells with all three compounds resulted in enhanced killing by macrophages. Only lipid A from bacterial cells exposed to compound 137 showed a 17% reduction in the level of decoration of lipid A with phosphoethanolamine by MALDI-TOF MS analysis and reduced stimulation of cytokine responses in THP-1 cells. Binding of 137 occurred with higher affinity to purified EptA than the starting material, as determined by 1D saturation transfer difference NMR. Treatment of eight MDR strains with 137 increased susceptibility to polymyxin B in all cases. Small molecules have been designed that bind to EptA, inhibit addition of phosphoethanolamine to lipid A and can sensitize N. gonorrhoeae to killing by macrophages.
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影响因子：
3.7
作者：
Piek S;Wang Z;Ganguly J;Lakey AM;Bartley SN;Mowlaboccus S;Anandan A;Stubbs KA;Scanlon MJ;Vrielink A;Azadi P;Carlson RW;Kahler CM
通讯作者：
Kahler CM
影响因子：
11.8
作者：
Lahra MM;Martin I;Demczuk W;Jennison AV;Lee KI;Nakayama SI;Lefebvre B;Longtin J;Ward A;Mulvey MR;Wi T;Ohnishi M;Whiley D
通讯作者：
Whiley D
DOI：
10.4049/jimmunol.1000953
发表时间：
2010-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Liu M;John CM;Jarvis GA
通讯作者：
Jarvis GA
影响因子：
4.9
作者：
Kandler, Justin L.;Joseph, Sandeep J.;Shafer, William M.
通讯作者：
Shafer, William M.
影响因子：
6.8
作者：
Kahler, Charlene M.;Sarkar-Tyson, Mitali;Vrielink, Alice
通讯作者：
Vrielink, Alice