小柯机器人

美国伊利诺伊大学香槟分校Paul J. Hergenrother研究小组发现，假单胞菌中不依赖孔蛋白的积累有助于发现抗生素。该研究于2023年11月22日在线发表于《自然》期刊。

在研究人员评估了345种不同化合物在铜绿假单胞菌（P. aeruginosa）和大肠杆菌中的全细胞积累情况。虽然某些带正电荷的化合物能同时渗透两种细菌，但P. aeruginosa比大肠杆菌更受限制。计算分析确定了与P. aeruginosa积累特别相关的小分子的独特理化性质，如形式电荷、正极性表面积和氢键供体表面积。吸收模式研究表明，大多数小分子通过一种不依赖于孔蛋白的途径渗透P. aeruginosa，从而发现了P. aeruginosa积累的通用趋势，这对未来抗生素的开发具有重要意义。回顾性抗生素实例证实了这些趋势，这些发现随后被应用于扩大仅对革兰氏阳性菌有效的抗生素夫西地酸的活性范围，使其对P. aeruginosa的抗菌活性显著提高。研究人员预计，这些发现将促进高渗透性抗假单胞菌药物的设计和开发。

据悉，由于对可在这些细菌体内蓄积的化合物类型缺乏了解，革兰氏阴性抗生素的开发一直受到阻碍。由于P. aeruginosa体内存在外排泵和底物特异性外膜孔蛋白，这种病原体的研究尤其具有挑战性。因此，P. aeruginosa感染几乎没有抗生素可供选择，而其众多的孔蛋白也使得发现通用积累指导方针的前景似乎不太可能。

附：英文原文

Title: Porin-independent accumulation in Pseudomonas enables antibiotic discovery

Author: Geddes, Emily J., Gugger, Morgan K., Garcia, Alfredo, Chavez, Martin Garcia, Lee, Myung Ryul, Perlmutter, Sarah J., Bieniossek, Christoph, Guasch, Laura, Hergenrother, Paul J.

Issue&Volume: 2023-11-22

Abstract: Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria1,2. The presence of efflux pumps and substrate-specific outer-membrane porins in Pseudomonas aeruginosa renders this pathogen particularly challenging3. As a result, there are few antibiotic options for P. aeruginosa infections4 and its many porins have made the prospect of discovering general accumulation guidelines seem unlikely5. Here we assess the whole-cell accumulation of 345 diverse compounds in P. aeruginosa and Escherichia coli. Although certain positively charged compounds permeate both bacterial species, P. aeruginosa is more restrictive compared to E. coli. Computational analysis identified distinct physicochemical properties of small molecules that specifically correlate with P. aeruginosa accumulation, such as formal charge, positive polar surface area and hydrogen bond donor surface area. Mode of uptake studies revealed that most small molecules permeate P. aeruginosa using a porin-independent pathway, thus enabling discovery of general P. aeruginosa accumulation trends with important implications for future antibiotic development. Retrospective antibiotic examples confirmed these trends and these discoveries were then applied to expand the spectrum of activity of a gram-positive-only antibiotic, fusidic acid, into a version that demonstrates a dramatic improvement in antibacterial activity against P. aeruginosa. We anticipate that these discoveries will facilitate the design and development of high-permeating antipseudomonals. We use a whole-cell accumulation assay to assess the ability of non-antibiotic, structurally diverse small molecules to accumulate in Pseudomonas aeruginosa, with potential application in developing drugs to target this pathogen.

DOI: 10.1038/s41586-023-06760-8

Source: https://www.nature.com/articles/s41586-023-06760-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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