背景:目前幽门螺杆菌感染的标准治疗方法,其中涉及两种广谱抗生素的组合,由于其对肠道微生物群的有害影响和耐药菌株的出现,因此面临着重大挑战。这凸显了开发新型反H.幽门螺杆菌药物。佐利妥,一种新型的细菌促旋酶抑制剂,目前正在接受治疗无并发症淋病奈瑟菌的全球III期临床试验。然而,没有关于其抗幽门螺杆菌活性的可用数据.
方法:我们评估了佐利沙星对具有多种多药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促旋酶超螺旋和微尺度热电泳测定,以鉴定幽门螺杆菌中佐利保星的靶标。我们分析了2262个幽门螺杆菌全基因组序列,以鉴定DNA促旋酶亚基B(GyrB)中的Asp424Asn和Lys445Asn突变,这些突变与唑列沙星抗性相关。
结果:佐利福沙星对所有测试的分离株都表现出有效的活性,最小抑制浓度(MIC)值范围为0.008至1μg/mL(MIC50:0.125μg/mL;MIC90:0.25μg/mL)。重要的是,没有证据表明幽门螺杆菌常用的4种一线抗生素存在交叉耐药.我们确定GyrB是唑列洛他星的主要靶标,与Asp424Asn或Lys445Asn取代赋予抗性。对2262个可用的幽门螺杆菌基因组的两个突变的筛选揭示了仅一个携带Asp424Asn取代的临床分离株。
结论:这些研究结果支持佐利沙星作为幽门螺杆菌治疗的有希望的候选药物的潜力,保证进一步的发展和评估。
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.
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.
CONCLUSIONS: These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.