An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics.
An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics.
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一种超敏感的微流体方法揭示了实验肽抗生素的物理化学和生物学活性之间的相关性。
DOI：
10.1038/s41598-022-07973-z
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发表时间：
2022-03-07
影响因子：
4.6
通讯作者：
Pagliara S
中科院分区：
文献类型：
--
作者：
Cama J;Al Nahas K;Fletcher M;Hammond K;Ryadnov MG;Keyser UF;Pagliara S
抗微生物药物耐药性挑战了现代医学控制感染的能力。鉴于对新型抗菌剂的迫切需求，多肽抗生素具有特别的前景。这些药物从细菌最暴露的部位——细胞膜开始，攻击细菌体内的多个目标。然而，在膜和细胞水平上量化多肽抗生素疗效的合适方法一直缺乏。本文采用两个互补的微流控平台，对两个实验系列多肽抗生素的构效关系进行了研究。我们揭示了每个肽在膜水平上的物理化学活性和细胞水平上的生物活性之间的强相关性。我们通过分析化合物在数百个单个巨型脂质囊泡上的膜分解活性，并通过单细胞分辨率定量克隆细菌群体内的表型反应来实现这一知识。事实证明，我们的策略能够检测到它们之间单个氨基酸取代的肽的差异反应，并可以加速肽抗菌药物的合理设计和开发。
Antimicrobial resistance challenges the ability of modern medicine to contain infections. Given the dire need for new antimicrobials, polypeptide antibiotics hold particular promise. These agents hit multiple targets in bacteria starting with their most exposed regions—their membranes. However, suitable approaches to quantify the efficacy of polypeptide antibiotics at the membrane and cellular level have been lacking. Here, we employ two complementary microfluidic platforms to probe the structure–activity relationships of two experimental series of polypeptide antibiotics. We reveal strong correlations between each peptide’s physicochemical activity at the membrane level and biological activity at the cellular level. We achieve this knowledge by assaying the membranolytic activities of the compounds on hundreds of individual giant lipid vesicles, and by quantifying phenotypic responses within clonal bacterial populations with single-cell resolution. Our strategy proved capable of detecting differential responses for peptides with single amino acid substitutions between them, and can accelerate the rational design and development of peptide antimicrobials.
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通过单侧链突变将细胞溶解纳米孔切成抗菌分形破裂。
影响因子：
17.1
作者：
Hammond K;Cipcigan F;Al Nahas K;Losasso V;Lewis H;Cama J;Martelli F;Simcock PW;Fletcher M;Ravi J;Stansfeld PJ;Pagliara S;Hoogenboom BW;Keyser UF;Sansom MSP;Crain J;Ryadnov MG
通讯作者：
Ryadnov MG
影响因子：
6.4
作者：
Goode O;Smith A;Zarkan A;Cama J;Invergo BM;Belgami D;Caño-Muñiz S;Metz J;O'Neill P;Jeffries A;Norville IH;David J;Summers D;Pagliara S
通讯作者：
Pagliara S
影响因子：
9.8
作者：
Attrill EL;Claydon R;Łapińska U;Recker M;Meaden S;Brown AT;Westra ER;Harding SV;Pagliara S
通讯作者：
Pagliara S
影响因子：
4.6
作者：
Henry, Theresa C.;Brynildsen, Mark P.
通讯作者：
Brynildsen, Mark P.
影响因子：
5.3
作者：
Cama J;Leszczynski R;Tang PK;Khalid A;Lok V;Dowson CG;Ebata A
通讯作者：
Ebata A