在 1928 年至 2023 年间全球 33213 株淋病奈瑟菌基因组中进行虚拟 gepotidacin 靶标挖掘，结合对 22 株具有不同 GyrA 和 ParC 取代的淋球菌分离株的 gepotidacin MIC 检测。
In silico gepotidacin target mining among 33 213 global Neisseria gonorrhoeae genomes from 1928 to 2023 combined with gepotidacin MIC testing of 22 gonococcal isolates with different GyrA and ParC substitutions.
机构信息
Institute for Global Health, Faculty of Population Health, University College London, London, UK.
WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
出版信息
J Antimicrob Chemother. 2024 Sep 3;79(9):2221-2226. doi: 10.1093/jac/dkae217.
OBJECTIVES
The novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations.
METHODS
We examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site.
RESULTS
GyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA.
CONCLUSIONS
In silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.
目的
新型双重靶标三氮杂吖辛， gepotidacin，最近在其治疗淋病的 III 期随机对照试验中显示出有前景的结果。我们通过对公开的全球基因组（n=33213）进行计算机挖掘，研究淋病奈瑟菌中 gepotidacin GyrA 和 ParC 靶标的变化，并确定与其他 GyrA 和/或 ParC 变化相结合的 GyrA A92 变化的分离株中的 gepotidacin MIC。
方法
我们检查了欧洲核苷酸档案中可用的淋病奈瑟菌 gyrA 和 parC 等位基因。使用琼脂稀释法（gepotidacin）或 Etest（四种抗生素）测定 MIC。从 AlphaFold 获得 DNA 回旋酶和拓扑异构酶 IV 的模型，并用于在结合部位模拟 gepotidacin。
结果
在 0.24%的基因组中发现了 GyrA A92 变化：GyrA A92P/S/V+S91F+D95Y/A/N（0.208%）、A92P+S91F（0.024%）和 A92P（0.003%），但未发现 A92T（先前与 gepotidacin 耐药相关）。在 10.6%的基因组中发现了 ParC D86 变化：ParC D86N/G（10.5%）、D86N+S87I（0.051%）、D86N+S88P（0.012%）和 D86G+E91G（0.003%）。一个分离株具有 GyrA A92P+ParC D86N 变化，但对 gepotidacin 仍敏感（MIC=0.125mg/L）。没有 GyrA 加上 ParC 变化导致 gepotidacin MIC>4mg/L。GyrA A92/A92T/A92P 结合 gepotidacin 的建模表明，由于 GyrA A92T 引起的 gepotidacin 耐药可能与与 DNA 形成新的极性接触有关。
结论
对 33213 个全球淋病奈瑟菌基因组（1928 年至 2023 年分离株）的计算机挖掘表明，GyrA 中的 A92 高度保守，而 ParC 的 D86 变化很常见。没有 GyrA 加上 ParC 变化导致 gepotidacin 耐药。MIC 测定和潜在抗菌药物耐药决定因素的基因组监测至关重要。
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