Convergent Evolution of Antibiotic Tolerance in Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia.
Convergent Evolution of Antibiotic Tolerance in Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia.
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DOI：
10.1128/iai.00001-22
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发表时间：
2022-04-21
影响因子：
3.1
通讯作者：
中科院分区：
文献类型：
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作者：
耐甲氧西林金黄色葡萄球菌(MRSA)引起的严重感染往往会并发持续性菌血症(PB)，尽管使用了积极的抗生素治疗。抗生素耐药性很少导致MRSA-PB，这表明抗生素耐药途径具有重要作用。为了确定与PB相关的细菌因素，我们对来自20名PB患者的206株MRSA分离株的全基因组进行了测序，并寻找宿主内适应性进化的遗传特征。我们发现，参与三羧酸循环(Citz和odhA)和严格反应(REL)的基因在多个感染中具有重复的、独立的、改变蛋白质的突变，表明趋同进化。这两条途径以前都与抗生素耐受性有关。CITZ的突变是最常见的，进一步的研究表明，它们通过失去柠檬酸合成酶活性而导致抗生素耐受。携带突变等位基因(CITZ、odhA和rel)的分离株从每个患者中以较低的频率采样，但在10名患者(50%)中被检测到。这些结果表明，在MRSA-PB期间，通常会出现耐药突变的亚群。耐甲氧西林金黄色葡萄球菌(MRSA)是医院获得性感染的主要原因。在严重的情况下，细菌侵入血液并导致菌血症，这是一种与高死亡率相关的情况。我们分析了来自菌血症患者的系列MRSA分离株的基因组，这些患者持续接受积极的抗生素治疗，并发现导致抗生素耐药的途径经常演变。抗生素耐药不同于抗生素耐药，耐受在抗生素治疗临床失败中的作用尚不清楚。我们的结果表明，遗传证据表明，特定代谢途径的扰动在MRSA在严重感染期间逃避抗生素的能力中发挥着重要作用。
Severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are often complicated by persistent bacteremia (PB) despite active antibiotic therapy. Antibiotic resistance rarely contributes to MRSA-PB, suggesting an important role for antibiotic tolerance pathways. To identify bacterial factors associated with PB, we sequenced the whole genomes of 206 MRSA isolates derived from 20 patients with PB and looked for genetic signatures of adaptive within-host evolution. We found that genes involved in the tricarboxylic acid cycle (citZ and odhA) and stringent response (rel) bore repeated, independent, protein-altering mutations across multiple infections, indicative of convergent evolution. Both pathways have been linked previously to antibiotic tolerance. Mutations in citZ were identified most frequently, and further study showed they caused antibiotic tolerance through the loss of citrate synthase activity. Isolates harboring mutant alleles (citZ, odhA, and rel) were sampled at a low frequency from each patient but were detected in 10 (50%) of the patients. These results suggest that subpopulations of antibiotic-tolerant mutants emerge commonly during MRSA-PB. Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital-acquired infection. In severe cases, bacteria invade the bloodstream and cause bacteremia, a condition associated with high mortality. We analyzed the genomes of serial MRSA isolates derived from patients with bacteremia that persisted through active antibiotic therapy and found a frequent evolution of pathways leading to antibiotic tolerance. Antibiotic tolerance is distinct from antibiotic resistance, and the role of tolerance in clinical failure of antibiotic therapy is defined poorly. Our results show genetic evidence that perturbation of specific metabolic pathways plays an important role in the ability of MRSA to evade antibiotics during severe infection.
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影响因子：
4.5
作者：
Gratani FL;Horvatek P;Geiger T;Borisova M;Mayer C;Grin I;Wagner S;Steinchen W;Bange G;Velic A;Maček B;Wolz C
通讯作者：
Wolz C
影响因子：
3.1
作者：
Altman DR;Sullivan MJ;Chacko KI;Balasubramanian D;Pak TR;Sause WE;Kumar K;Sebra R;Deikus G;Attie O;Rose H;Lewis M;Fulmer Y;Bashir A;Kasarskis A;Schadt EE;Richardson AR;Torres VJ;Shopsin B;van Bakel H
通讯作者：
van Bakel H
影响因子：
14.9
作者：
Letunic I;Bork P
通讯作者：
Bork P
影响因子：
6.4
作者：
Fey PD;Endres JL;Yajjala VK;Widhelm TJ;Boissy RJ;Bose JL;Bayles KW
通讯作者：
Bayles KW
影响因子：
12.3
作者：
Giulieri SG;Baines SL;Guerillot R;Seemann T;Gonçalves da Silva A;Schultz M;Massey RC;Holmes NE;Stinear TP;Howden BP
通讯作者：
Howden BP