Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus.
Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus.
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DOI：
10.1039/d1sc04283a
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发表时间：
2021-11-10
期刊：
影响因子：
8.4
通讯作者：
Boros E
中科院分区：
文献类型：
--
作者：
Pandey A;Śmiłowicz D;Boros E
铁载体-抗生素药物缀合物被认为是递送和增强抗生素的抗菌活性的有效工具，但只有少数人在临床前和临床上取得了成功。在这里，我们介绍了镓（iii）配合物的环丙沙星功能化的线性去铁色素，加波沙星，与一个可裂解的丝氨酸连接作为一个有效的治疗S。金黄色葡萄球菌感染。我们采用体外抑制试验，放射化学，示踪剂为基础的摄取和药代动力学评估我们的铅化合物，最终在体内疗效研究中的软组织感染模型的表征。加波沙星在野生型S中表现出最小抑制浓度（MIC 98）93 nM。金黄色葡萄球菌，超过母体抗生素环丙沙星（0.9 μM）的效力。加波沙星是一种蛋白酶底物，可以在细菌细胞质中释放抗生素有效负载。野生型细菌菌株的放射化学实验表明，67加波沙星是有效地利用铁载体介导的，主动摄取。67-Galbofloxacin在小鼠肌肉注射沙门氏菌模型中的生物分布。金黄色葡萄球菌感染显示肾清除率和感染肌肉中的摄取增强，与67 Ga-柠檬酸盐相比，其显示无选择性。随后的体内药物治疗研究揭示了S.金黄色葡萄球菌感染负荷和持续生存7天的加波沙星。环丙沙星在相同的分子剂量（9.3 μmol kg−1）下没有治疗效果，并导致所有研究动物在24小时内死亡。总之，有利的细菌生长抑制、药代动力学和体内功效特性使加波沙星成为第一个合理设计的用于管理S.金黄色葡萄球菌感染。Galbofloxacin是一种新型的治疗诊断用异铁载体抗生素，在抗沙门氏菌方面表现出无与伦比的效力。体内金黄色葡萄球菌感染。
Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(iii) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for S. aureus bacterial infections. We employed characterization using in vitro inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in in vivo efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC98) 93 nM in wt S. aureus, exceeding the potency of the parent antibiotic ciprofloxacin (0.9 μM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with wt bacterial strains reveal that 67Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of 67Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to 67Ga-citrate, which showed no selectivity. A subsequent in vivo drug therapy study reveals efficient reduction in S. aureus infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 μmol kg−1) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and in vivo efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of S. aureus bacterial infections. Galbofloxacin, a novel theranostic xenosiderophore antibiotic, exhibits unparalleled potency in combating S. aureus infections in vivo.
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影响因子：
4.9
作者：
Adams CJ;Wilson JJ;Boros E
通讯作者：
Boros E
DOI：
10.1111/j.1432-1033.1979.tb13283.x
发表时间：
1979-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
HARTMANN, A;FIEDLER, HP;BRAUN, V
通讯作者：
BRAUN, V
影响因子：
3.3
作者：
Arnold, Carolyn E.;Bordin, Angela;Cohen, Noah D.
通讯作者：
Cohen, Noah D.
n5-acetyl-n5-hydroxy-l-ornithine-derived siderophore beta-lactam conjugates 的合成、嗜酸性物质和抗菌活性--铁传输介导的药物输送
影响因子：
7.3
作者：
DOLENCE, EK;MINNICK, AA;PAYNE, SM
通讯作者：
PAYNE, SM
影响因子：
4.2
作者：
Juarez-Hernandez, Raul E.;Miller, Patricia A.;Miller, Marvin J.
通讯作者：
Miller, Marvin J.