A Chimeric Penicillin Binding Protein 2X Significantly Decreases in Vitro Beta-Lactam Susceptibility and Increases in Vivo Fitness of Streptococcus pyogenes.
A Chimeric Penicillin Binding Protein 2X Significantly Decreases in Vitro Beta-Lactam Susceptibility and Increases in Vivo Fitness of Streptococcus pyogenes.
复制标题
嵌合青霉素结合蛋白 2X 显着降低化脓性链球菌的体外 β-内酰胺敏感性并增加体内适应性。
DOI：
10.1016/j.ajpath.2022.06.011
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Musser,JamesM
中科院分区：
文献类型：
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作者：
Olsen,RandallJ;Zhu,Luchang;Mangham,ReganE;Faili,Ahmad;Kayal,Samer;Beres,StephenB;Musser,JamesM
所有供试的化脓性链球菌（A组链球菌，GAS）对青霉素敏感。然而，最近已经鉴定出青霉素结合蛋白中具有氨基酸取代的GAS菌株，所述氨基酸取代赋予对β-内酰胺抗生素的敏感性降低。这一发现引起了人们对GAS中β-内酰胺抗生素耐药性的担忧。全基因组测序最近鉴定了具有嵌合青霉素结合蛋白2X（PBP 2X）的GAS菌株，所述嵌合青霉素结合蛋白2X（PBP 2X）含有来自停乳链球菌亚种类马链球菌（SDSE）的重组片段。为了直接测试嵌合SDSE样PBP 2X改变β-内酰胺体外和体内适应性的假设，产生了同基因突变株，并在坏死性肌炎的小鼠模型中评估了毒力。与具有野生型GAS样PBP 2X的天然存在的和同基因的菌株相比，具有嵌合SDSE样PBP 2X的菌株在体外对9种β-内酰胺类抗生素的耐受性降低。在坏死性肌炎的小鼠模型中，在没有苄青霉素治疗的情况下，菌株具有相同的适应性。然而，间歇性接受亚治疗剂量的青霉素治疗的小鼠，从感染嵌合SDSE样PBP 2X菌株的四肢中回收的菌落形成单位显着更多。这些结果表明，PBP 2X嵌合体等突变可能导致β-内酰胺敏感性显著降低，适应性和毒力增加。需要扩大诊断实验室监测、基因组测序和GAS中潜在的β-内酰胺类抗生素耐药性的分子发病机制研究。
All tested strains ofStreptococcus pyogenes(group A streptococcus, GAS) remain susceptible to penicillin. However, GAS strains with amino acid substitutions in penicillin-binding proteins that confer decreased susceptibility to beta-lactam antibiotics have been identified recently. This discovery raises concerns about emergence of beta-lactam antibiotic resistance in GAS. Whole genome sequencing recently identified GAS strains with a chimeric penicillin-binding protein 2X (PBP2X) containing a recombinant segment fromStreptococcus dysgalactiaesubspeciesequisimilis(SDSE). To directly test the hypothesis that the chimeric SDSE-like PBP2X alters beta-lactam susceptibilityin vitroand fitnessin vivo, an isogenic mutant strain was generated and virulence assessed in a mouse model of necrotizing myositis. Compared with naturally occurring and isogenic strains with a wild-type GAS-like PBP2X, strains with the chimeric SDSE-like PBP2X had reduced susceptibilityin vitroto nine beta-lactam antibiotics. In a mouse model of necrotizing myositis, the strains had identical fitness in the absence of benzylpenicillin treatment. However, mice treated intermittently with a subtherapeutic dose of benzylpenicillin had significantly more colony-forming units recovered from limbs infected with strains with the chimeric SDSE-like PBP2X. These results show that mutations such as the PBP2X chimera may result in significantly decreased beta-lactam susceptibility and increased fitness and virulence. Expanded diagnostic laboratory surveillance, genome sequencing, and molecular pathogenesis study of potentially emergent beta-lactam antibiotic resistance among GAS are needed.