GaSal-2：一种靶向细胞外血球HasAp的水溶性抗假单胞菌剂。

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-07-29 DOI:10.1021/acsinfecdis.5c00296

Aziza Frank, Lucia Hwang, William T. Witt, Garrick Centola, Kieran Johnson, Yong Ai, Emel Sen-Kilic, Gage M. Pyles, Annalisa B. Huckaby, Catherine B. Blackwood, Sarah Jo Miller, S. Matthew Hudson, Kellie Hom, Wenbo Yu, Alexander D. MacKerell Jr., Mariette Barbier, Angela Wilks* and Fengtian Xue*,

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引用次数: 0

摘要

耐多药铜绿假单胞菌是一种重要的病原体，需要新的抗生素。在P. aeruginosa感染过程中，胞外血球hasAp及其外膜受体hasR是最显著上调的基因。铜绿假单胞菌ΔhasR菌株表现出明显的生长和毒力降低。我们之前描述了一种镓salophen复合物GaSal，它通过靶向HasAp显示出抗假单胞菌的潜力。在这里，我们报道了一种水溶性衍生物GaSal-2的发展，它与HasAp紧密结合，阻断细菌细胞表面信号级联的转录激活，抑制铜绿假单胞菌的生长，并有效地破坏铜绿假单胞菌建立的生物膜。此外，GaSal-2对人肺成纤维细胞和肝细胞没有毒性。它在小鼠肺部感染模型中显示出有希望的抗假单胞菌作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp

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GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp

Multidrug-resistant Pseudomonas aeruginosa is a critical pathogen that demands new antibiotics. During P. aeruginosa infection, the extracellular hemophore hasAp and its outer membrane receptor hasR are the most dramatically upregulated genes. The P. aeruginosa ΔhasR strain exhibits significantly reduced growth and virulence. We previously described a gallium salophen complex GaSal that demonstrated antipseudomonal potential by targeting HasAp. Here, we report the development of a water-soluble derivative, GaSal-2, which tightly binds to HasAp, blocks transcriptional activation of the bacterial cell surface signaling cascade, inhibits P. aeruginosa growth, and effectively disrupts P. aeruginosa established biofilms. Moreover, GaSal-2 is not toxic to human lung fibroblasts and hepatocytes. It has shown promising antipseudomonal effects in a murine lung infection model.

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.