Antimicrobial Activity of Brilacidin against E. coli.

IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL
ACS Infectious Diseases Pub Date : 2025-06-13 Epub Date: 2025-06-03 DOI:10.1021/acsinfecdis.5c00023
Michael J Wilhelm, Mohammad Sharifian Gh, Bruk Mensa, Gabriella L Howell, William F DeGrado, Hai-Lung Dai
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Abstract

Brilacidin (BRI) is a potent small-molecule mimic of antimicrobial peptides that has demonstrated efficacy against various pathogens. To better understand its antimicrobial mechanism of action, we investigated the interactions of BRI with the membranes of Escherichia coli. Specifically, the surface-sensitive nonlinear optical technique, second harmonic laser scattering (SHS), was used to monitor BRI-induced changes in the permeabilities of the dual phospholipid membranes of E. coli by measuring the adsorption and transport of a membrane-permeable indicator molecule (the quaternary ammonium cation, malachite green). Following exposure to 0.6 to 12× MIC BRI, the permeability of the outer membrane was shown to increase 2-fold. Conversely, the permeability of the inner membrane was shown to exhibit more complicated behavior: Permeability increased for near-MIC doses (≤3× MIC) of BRI but was significantly reduced for higher concentrations. The latter is consistent with the depolarization of the inner membrane, which was previously predicted in a computational study. The interpretation of the SHS results was corroborated with complementary assays that measure the permeability of small polar molecules to periplasmic versus cytosolic enzymes, as well as ATP luminescence and Western blot assays (for accumulation of secreted protein precursors). It is suggested that the mechanism of action of BRI against E. coli consists of a sequential and complementary attack on both membranes, beginning with an immediate and persistent increase in the permeability of the outer membrane and followed by likely depolarization of the inner membrane. This study also illustrates a new quantitative capability for monitoring antimicrobial interactions by using time-resolved SHS.

砖酸素对大肠杆菌的抑菌活性研究。
Brilacidin (BRI)是一种有效的小分子抗菌肽模拟物,已证明对多种病原体有效。为了更好地了解其抗菌作用机制,我们研究了BRI与大肠杆菌膜的相互作用。具体而言,利用表面敏感非线性光学技术——二次谐波激光散射(SHS),通过测量一种膜透性指示分子(季铵盐阳离子、孔雀石绿)的吸附和转运,监测了bri诱导的大肠杆菌双磷脂膜透性的变化。暴露于0.6至12倍MIC BRI后,外膜的通透性增加了2倍。相反,内膜的通透性表现出更复杂的行为:在接近MIC剂量(≤3倍MIC)的BRI中,通透性增加,但在较高浓度下,通透性显著降低。后者与先前在计算研究中预测的内膜去极化一致。SHS结果的解释得到了补充分析的证实,这些分析测量了小极性分子对质周酶和胞质酶的渗透性,以及ATP发光和Western blot分析(用于分泌蛋白前体的积累)。这表明,BRI对大肠杆菌的作用机制包括对两种膜的连续和互补攻击,首先是外膜通透性的立即和持续增加,然后是内膜可能的去极化。这项研究还说明了一种新的定量能力,通过使用时间分辨SHS监测抗菌药物相互作用。
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来源期刊
ACS Infectious Diseases
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.
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