Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in P. aeruginosa biofilms.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Oliver J Hills, Isaac O K Noble, Alex Heyam, Andrew J Scott, James Smith, Helen F Chappell
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Abstract

Intravenous gallium nitrate therapy is a novel therapeutic strategy deployed to combat chronic Pseudomonas aeruginosa biofilm infections in the lungs of cystic fibrosis (CF) patients by interfering with iron (Fe3+) uptake. The therapy is a source of Ga3+, which competes with Fe3+ for siderophore binding, subsequently disrupting iron metabolism and inhibiting biofilm proliferation in vivo. It was recently demonstrated that the Pseudomonas quinolone signal (PQS) can chelate Fe3+ to assist in bacterial iron uptake. However, it is unknown whether exogenous gallium also targets [Fe(PQS)3] uptake, which, in turn, would extend the mechanism of gallium therapy beyond siderophore competition, potentially supporting use of the therapy against P. aeruginosa mutants deficient in siderophore uptake proteins. To that end, the thermodynamic feasibility of iron-for-gallium cation exchange into [Fe(PQS)3] was evaluated using quantum chemical density functional theory (DFT) modelling and verified experimentally using 1H nuclear magnetic resonance (NMR). We demonstrate here that Ga3+ can strongly bind to three PQS molecules and, furthermore, displace and substitute Fe3+ from the native chelate pocket within PQS complexes, through a Trojan horse mechanism, retaining the key structural features present within the native ferric complex. As such, [Fe(PQS)3] complexes, in addition to ferric-siderophore complexes, represent another target for gallium therapy.

原子模型和核磁共振研究显示,镓可以靶向铜绿微囊藻生物膜中的铁质 PQS 吸收系统。
静脉注射硝酸镓疗法是一种新的治疗策略,通过干扰铁(Fe3+)的吸收来对抗囊性纤维化(CF)患者肺部的慢性铜绿假单胞菌生物膜感染。这种疗法是 Ga3+ 的一种来源,Ga3+ 与 Fe3+ 竞争苷元结合,从而破坏铁代谢,抑制体内生物膜的增殖。最近有研究表明,假单胞菌喹诺酮信号(PQS)可以螯合 Fe3+,帮助细菌吸收铁。然而,外源镓是否也能靶向[Fe(PQS)3]摄取尚不得而知,而这反过来又会将镓疗法的机制扩展到嗜苷酸竞争之外,从而有可能支持利用这种疗法来对付缺乏嗜苷酸盐摄取蛋白的铜绿假单胞菌突变体。为此,我们利用量子化学密度泛函理论(DFT)建模评估了[Fe(PQS)3]中铁-镓阳离子交换的热力学可行性,并利用 1H 核磁共振(NMR)进行了实验验证。我们在此证明,Ga3+ 能与三个 PQS 分子紧密结合,而且还能通过特洛伊木马机制将 Fe3+ 从 PQS 复合物的原生螯合剂袋中置换出来,并保留原生铁复合物的关键结构特征。因此,[Fe(PQS)3] 复合物是除铁苷复合物之外的另一个镓治疗目标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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