PDF(Pubmed)
Abstract：
The mec-independent oxacillin non-susceptible S. aureus (MIONSA) strains represent a great clinical challenge, as they are not easily detected and can lead to treatment failure. However, the responsible molecular mechanisms are still very little understood. Here, we studied four clinical ST8-MSSA-t024 isolates recovered during the course of antibiotic treatment from a patient suffering successive episodes of bacteremia. The first isolates (SAMS1, SAMS2, and SAMS3) were susceptible to cefoxitin and oxacillin. The last one (SA2) was susceptible to cefoxitin, resistant to oxacillin, lacked mec genes, and had reduced susceptibility to teicoplanin. SA2 showed higher β-lactamase activity than SAMS1. However, β-lactamase hyperproduction could not be linked to oxacillin resistance as it was not inhibited by clavulanic acid, and no genetic changes that could account for its hyperproduction were found. Importantly, we hereby report the in vivo acquisition and coexistence of different adaptive mutations in genes associated with peptidoglycan synthesis (pbp2, rodA, stp1, yjbH, and yvqF/vraT), which is possibly related with the development of oxacillin resistance and reduced susceptibility to teicoplanin in SA2. Using three-dimensional models and PBP binding assays, we demonstrated the high contribution of the SA2 PBP2 Ala450Asp mutation to the observed oxacillin resistance phenotype. Our results should be considered as a warning for physicians and microbiologists in the region, as MIONSA detection and treatment represent an important clinical challenge.
摘要：
非mec依赖性苯唑西林非易感金黄色葡萄球菌（MIONSA）菌株代表了巨大的临床挑战，因为它们不容易被发现，并且可能导致治疗失败。然而,负责任的分子机制仍然知之甚少。这里,我们研究了在抗生素治疗过程中从连续发生菌血症的患者中回收的4种临床ST8-MSSA-t024分离株.第一批分离株（SAMS1，SAMS2和SAMS3）对头孢西丁和苯唑西林敏感。最后一个（SA2）对头孢西丁敏感，耐苯唑西林,缺少mec基因,对替考拉宁的敏感性降低。SA2显示出比SAMS1更高的β-内酰胺酶活性。然而,β-内酰胺酶的高产量与苯唑西林耐药性无关，因为它不受克拉维酸的抑制，没有发现可以解释其高产的遗传变化。重要的是,我们特此报告与肽聚糖合成相关的基因中不同适应性突变的体内获取和共存（pbp2，rodA，stp1,yjbH,和yvqF/vraT)，这可能与SA2中苯唑西林耐药性的发展和对替考拉宁的敏感性降低有关。使用三维模型和PBP结合测定，我们证明了SA2PBP2Ala450Asp突变对观察到的苯唑西林耐药表型的高贡献.我们的结果应该被视为对该地区医生和微生物学家的警告，作为MIONSA的检测和治疗代表了重要的临床挑战。
