Antibody-recruiting protein-catalyzed capture agents to combat antibiotic-resistant bacteria.
Antibody-recruiting protein-catalyzed capture agents to combat antibiotic-resistant bacteria.
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DOI：
10.1039/c9sc04842a
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发表时间：
2020-02-12
期刊：
影响因子：
8.4
通讯作者：
Heath JR
中科院分区：
文献类型：
--
作者：
Idso MN;Akhade AS;Arrieta-Ortiz ML;Lai BT;Srinivas V;Hopkins JP Jr;Gomes AO;Subramanian N;Baliga N;Heath JR
预计到2050年，抗生素耐药性感染将导致1000多万人死亡，但新抗生素的开发速度却有所放缓。这表明迫切需要快速开发针对新出现的耐药病原体的抗生素的方法。我们报告了一种通用的计算和合成相结合的方法，称为抗体招募蛋白催化捕获剂（AR-PCCs），以解决这一挑战。我们应用组合蛋白催化捕获剂（PCC）技术鉴定了碳青霉烯耐药肺炎克雷伯菌（一种具有耐药菌株的机会性革兰氏阴性病原体）高度保守的表面蛋白表位的大环肽配体。多组学数据结合生物信息学分析确定了肺炎克雷伯菌高表达MrkA表面蛋白的表位，用于PCC筛选。表现最好的配体对全长MrkA表现出高亲和力（EC50 ~ 50 nM），并选择性地与表达MrkA的肺炎克雷伯菌结合，但不与其他致病菌结合。携带半抗原片段的AR-PCCs促进了针对肺炎克雷伯菌的抗体募集，导致巨噬细胞的吞噬和吞噬杀伤增强。这种高度靶向抗生素的快速发展意味着这里描述的综合计算和合成工具包可用于加速生产针对耐药细菌的抗生素。抗体招募蛋白催化捕获剂（AR-PCCs）是一类新型的全合成高靶向抗生素，可招募内源性免疫反应来消除耐药微生物。
Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting protein-catalyzed capture agents (AR-PCCs), to address this challenge. We applied the combinatorial protein catalyzed capture agent (PCC) technology to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic Gram-negative pathogen with drug resistant strains. Multi-omic data combined with bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing ligand exhibited high-affinity (EC50 ∼50 nM) to full-length MrkA, and selectively bound to MrkA-expressing K. pneumoniae, but not to other pathogenic bacterial species. AR-PCCs that bear a hapten moiety promoted antibody recruitment to K. pneumoniae, leading to enhanced phagocytosis and phagocytic killing by macrophages. The rapid development of this highly targeted antibiotic implies that the integrated computational and synthetic toolkit described here can be used for the accelerated production of antibiotics against drug resistant bacteria. Antibody-recruiting protein-catalyzed capture agent (AR-PCCs) are a new class of all-synthetic and highly targeted antibiotics that recruit endogenous immune responses to eliminate drug-resistant microbes.
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影响因子：
9.9
作者：
Arrieta-Ortiz ML;Hafemeister C;Bate AR;Chu T;Greenfield A;Shuster B;Barry SN;Gallitto M;Liu B;Kacmarczyk T;Santoriello F;Chen J;Rodrigues CD;Sato T;Rudner DZ;Driks A;Bonneau R;Eichenberger P
通讯作者：
Eichenberger P
影响因子：
2.8
作者：
Blumer, C;Kleefeld, A;Unden, G
通讯作者：
Unden, G
影响因子：
3.6
作者：
Cowles CE;Li Y;Semmelhack MF;Cristea IM;Silhavy TJ
通讯作者：
Silhavy TJ
影响因子：
64.5
作者：
Dotiwala F;Sen Santara S;Binker-Cosen AA;Li B;Chandrasekaran S;Lieberman J
通讯作者：
Lieberman J
影响因子：
4
作者：
Fura, Jonathan M.;Sabulski, Mary J.;Pires, Marcos M.
通讯作者：
Pires, Marcos M.