Evaluating the potency of zoliflodacin against Helicobacter pylori: In vitro activity and conserved GyrB target

IF 4.3 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Helicobacter Pub Date : 2024-04-16 DOI:10.1111/hel.13075

Jing Liu, Jia Jia, Ting Shi, Yuefan Bai, Yanqiang Huang, Liping Zeng, Hongkai Bi

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引用次数: 0

Abstract

Background

The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its detrimental impact on the gut microbiota and the emergence of drug-resistant strains. This underscores the urgent requirement for the development of novel anti-H. pylori drugs. Zoliflodacin, a novel bacterial gyrase inhibitor, is currently undergoing global phase III clinical trials for treating uncomplicated Neisseria gonorrhoeae. However, there is no available data regarding its activity against H. pylori.

Materials and Methods

We evaluated the in vitro activity of zoliflodacin against H. pylori clinical isolates (n = 123) with diverse multidrug resistance. We performed DNA gyrase supercoiling and microscale thermophoresis assays to identify the target of zoliflodacin in H. pylori. We analyzed 2262 H. pylori whole genome sequences to identify Asp424Asn and Lys445Asn mutations in DNA gyrase subunit B (GyrB) that are associated with zoliflodacin resistance.

Results

Zoliflodacin exhibits potent activity against all tested isolates, with minimal inhibitory concentration (MIC) values ranging from 0.008 to 1 μg/mL (MIC₅₀: 0.125 μg/mL; MIC₉₀: 0.25 μg/mL). Importantly, there was no evidence of cross-resistance to any of the four first-line antibiotics commonly used against H. pylori. We identified GyrB as the primary target of zoliflodacin, with Asp424Asn or Lys445Asn substitutions conferring resistance. Screening of 2262 available H. pylori genomes for the two mutations revealed only one clinical isolate carrying Asp424Asn substitution.

Conclusion

These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.

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评估佐利氟达星抗幽门螺旋杆菌的效力：体外活性和保守的 GyrB 靶点

背景幽门螺旋杆菌感染目前的标准治疗方法是联合使用两种广谱抗生素，但由于这种方法对肠道微生物群的有害影响以及耐药菌株的出现，这种方法面临着巨大的挑战。这凸显了开发新型抗幽门螺杆菌药物的迫切需求。新型细菌回旋酶抑制剂 Zoliflodacin 目前正在全球进行 III 期临床试验，用于治疗无并发症的淋病奈瑟菌。然而，目前还没有关于它对幽门螺杆菌活性的数据。材料与方法我们评估了佐利氟达星对具有多种耐药性的幽门螺杆菌临床分离株（n = 123）的体外活性。我们进行了DNA回旋酶超螺旋和微尺度热泳检测，以确定佐利氟达星在幽门螺杆菌中的靶点。我们分析了2262个幽门螺杆菌全基因组序列，以确定DNA回旋酶亚基B（GyrB）中与佐利氟达星耐药性相关的Asp424Asn和Lys445Asn突变。结果佐利氟达星对所有测试的分离菌株都具有强效活性，最小抑菌浓度 (MIC) 值范围为 0.008 至 1 μg/mL（MIC50：0.125 μg/mL；MIC90：0.25 μg/mL）。重要的是，没有证据表明幽门螺杆菌对常用的四种一线抗生素产生交叉耐药性。我们发现GyrB是佐利氟达星的主要作用靶点，Asp424Asn或Lys445Asn取代可产生抗药性。对现有的 2262 个幽门螺杆菌基因组进行这两种突变筛查后发现，只有一个临床分离株携带 Asp424Asn 取代。结论这些发现支持了佐立氟达辛作为幽门螺杆菌治疗候选药物的潜力，值得进一步开发和评估。

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

Helicobacter 医学-微生物学

CiteScore

8.40

自引率

9.10%

发文量

审稿时长

2 months

期刊介绍： Helicobacter is edited by Professor David Y Graham. The editorial and peer review process is an independent process. Whenever there is a conflict of interest, the editor and editorial board will declare their interests and affiliations. Helicobacter recognises the critical role that has been established for Helicobacter pylori in peptic ulcer, gastric adenocarcinoma, and primary gastric lymphoma. As new helicobacter species are now regularly being discovered, Helicobacter covers the entire range of helicobacter research, increasing communication among the fields of gastroenterology; microbiology; vaccine development; laboratory animal science.