A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae.
A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae.
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DOI：
10.1128/aac.00251-22
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发表时间：
2022-05-17
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
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作者：
对一线抗生素耐药的淋病奈瑟菌分离株的持续出现重新激发了人们对替代疗法的兴趣，例如扩大使用庆大霉素（Gen）。我们假设Gen的广泛使用促进了对该氨基糖苷类药物具有临床耐药性的淋球菌的出现。为了了解淋球菌对Gen的敏感性如何降低，我们选择了Gen敏感菌株FA 19的自发低水平Gen耐药（GenR）突变体（Gen MIC = 32 μg/mL）。因此，我们在编码延伸因子G（EF-G）的fusA中发现了一种新型错义突变，导致EF-G结构域IV中第563位氨基酸位置的丙氨酸（A）替换为缬氨酸（V）;该突变等位基因被称为fusA 2。转化分析表明，fusA 2可使Gen MIC提高4倍。虽然拥有fusA 2不会损害体外淋球菌生长或蛋白质合成，但在雌性小鼠下生殖道实验感染期间，它确实导致了健身缺陷。通过对10，634株国际淋球菌临床分离株的全基因组序列进行生物信息学分析，经常检测到其他fusA等位基因，但遗传学研究表明，它们不能以与fusA 2相似的方式降低Gen易感性。与这些不同的国际fusA等位基因相反，仅在单一淋球菌临床分离株中检测到fusA 2编码的A563 V置换。我们推测fusA 2在N.淋病临床分离株的基因突变可能是由于感染期间的适应性成本，但减轻这种适应性成本的补偿性突变可能会出现并促进全球菌株中的GenR。
The continued emergence of Neisseria gonorrhoeae isolates which are resistant to first-line antibiotics has reinvigorated interest in alternative therapies such as expanded use of gentamicin (Gen). We hypothesized that expanded use of Gen promotes emergence of gonococci with clinical resistance to this aminoglycoside. To understand how decreased susceptibility of gonococci to Gen might develop, we selected spontaneous low-level Gen-resistant (GenR) mutants (Gen MIC = 32 μg/mL) of the Gen-susceptible strain FA19. Consequently, we identified a novel missense mutation in fusA, which encodes elongation factor G (EF-G), causing an alanine (A) to valine (V) substitution at amino acid position 563 in domain IV of EF-G; the mutant allele was termed fusA2. Transformation analysis showed that fusA2 could increase the Gen MIC by 4-fold. While possession of fusA2 did not impair either in vitro gonococcal growth or protein synthesis, it did result in a fitness defect during experimental infection of the lower genital tract in female mice. Through bioinformatic analysis of whole-genome sequences of 10,634 international gonococcal clinical isolates, other fusA alleles were frequently detected, but genetic studies revealed that they could not decrease Gen susceptibility in a similar manner to fusA2. In contrast to these diverse international fusA alleles, the fusA2-encoded A563V substitution was detected in only a single gonococcal clinical isolate. We hypothesize that the rare occurrence of fusA2 in N. gonorrhoeae clinical isolates is likely due to a fitness cost during infection, but compensatory mutations which alleviate this fitness cost could emerge and promote GenR in global strains.
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影响因子：
--
作者：
Dillard JP
通讯作者：
Dillard JP
开放式细菌种群基因组学：BIGSDB软件，pubmlst.org网站及其应用。
影响因子：
--
作者：
Jolley KA;Bray JE;Maiden MCJ
通讯作者：
Maiden MCJ
影响因子：
3.1
作者：
Mann LM;Kirkcaldy RD;Papp JR;Torrone EA
通讯作者：
Torrone EA
影响因子：
5.2
作者：
Ibacache-Quiroga, Claudia;Oliveros, Juan C.;Blazquez, Jesus
通讯作者：
Blazquez, Jesus
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.