Department of Microbiology, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing, Chongqing, China.
Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University, Chongqing, China.
mBio. 2019 Jun 11;10(3):e00880-19. doi: 10.1128/mBio.00880-19.
Methicillin-resistant (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (, to [-]) was upregulated in MRSA in response to subinhibitory concentrations of β-lactam induction. The increasing expression of by β-lactams was directly controlled by the global regulator SarA. The β-lactam-induced Lpls stimulated the production of interleukin-6 and tumor necrosis factor alpha in RAW 264.7 macrophages. The deletion mutants (N315Δ and USA300Δ) decreased the proinflammatory cytokine levels and Purified lipidated SA2275-his proteins could trigger a Toll-like-receptor-2 (TLR2)-dependent immune response in primary mouse bone marrow-derived macrophages and C57BL/6 mice. The bacterial loads of N315Δ in the mouse kidney were lower than those of the wild-type N315. The β-lactam-treated MRSA exacerbated cutaneous infections in both BALB/c and C57BL/6 mice, presenting increased lesion size; destroyed skin structure; and easily promoted abscess formation compared with those of the untreated MRSA. However, the size of abscesses caused by the β-lactam-treated N315 was negligibly different from those caused by the untreated N315Δ in C57BL/6 TLR2 mice. Our findings suggest that β-lactams must be used carefully because they might aggravate the outcome of MRSA infection compared to inaction in treatment. β-Lactam antibiotics are widely applied to treat infectious diseases. However, certain poor disease outcomes caused by β-lactams remain poorly understood. In this study, we have identified a cluster of lipoprotein-like genes (, -) that is upregulated in the major clinically prevalent MRSA clones in response to subinhibitory concentrations of β-lactam induction. The major highlight of this work is that β-lactams stimulate the expression of SarA, which directly binds to the cluster promoter region and upregulates expression in MRSA. Deletion of significantly decreases proinflammatory cytokine levels and The β-lactam-induced Lpls enhance host inflammatory responses by triggering the Toll-like-receptor-2-mediated expressions of interleukin-6 and tumor necrosis factor alpha. The β-lactam-induced Lpls are important virulence factors that enhance MRSA pathogenicity. These data elucidate that subinhibitory concentrations of β-lactams can exacerbate the outcomes of MRSA infection through induction of controlled by the global regulator SarA.
耐甲氧西林金黄色葡萄球菌（MRSA）几乎可以抵抗所有具有杀菌活性的β-内酰胺类抗生素。然而，经验性使用的β-内酰胺类抗生素是否会增强 MRSA 的致病性尚不清楚。在这项研究中，我们发现，一组脂蛋白样基因（ 至 ）在 MRSA 中被上调，以响应亚抑菌浓度的β-内酰胺诱导。β-内酰胺类药物通过全局调节剂 SarA 直接控制 的表达增加。β-内酰胺诱导的 Lpls 刺激 RAW 264.7 巨噬细胞中白细胞介素-6 和肿瘤坏死因子-α的产生。缺失突变体（N315Δ和 USA300Δ）降低了促炎细胞因子水平 纯化的脂化 SA2275-his 蛋白可在原代小鼠骨髓来源的巨噬细胞和 C57BL/6 小鼠中触发 Toll 样受体-2（TLR2）依赖性免疫反应。与野生型 N315 相比，N315Δ 在小鼠肾脏中的细菌载量较低。β-内酰胺类药物处理的 MRSA 在 BALB/c 和 C57BL/6 小鼠中加重了皮肤感染，表现为病变大小增加；破坏皮肤结构；并且与未经处理的 MRSA 相比，容易促进脓肿形成。然而，β-内酰胺类药物处理的 N315 引起的脓肿大小与 TLR2 小鼠中未经处理的 N315Δ 引起的脓肿大小几乎没有差异。我们的研究结果表明，与不治疗相比，β-内酰胺类药物在治疗 MRSA 感染方面可能会加重病情，因此必须谨慎使用。β-内酰胺类抗生素被广泛应用于治疗感染性疾病。然而，某些由β-内酰胺类药物引起的不良疾病结局仍知之甚少。在这项研究中，我们已经确定了一组脂蛋白样基因（ 至 ），这些基因在主要的临床流行的 MRSA 克隆中被上调，以响应亚抑菌浓度的β-内酰胺诱导。这项工作的主要亮点是，β-内酰胺类药物刺激 SarA 的表达，SarA 直接结合到 簇启动子区域，并上调 MRSA 中的 表达。缺失 显著降低促炎细胞因子水平 和 诱导的 Lpls 通过触发 Toll 样受体-2 介导的白细胞介素-6 和肿瘤坏死因子-α的表达来增强宿主炎症反应。β-内酰胺诱导的 Lpls 是增强 MRSA 致病性的重要毒力因子。这些数据表明，亚抑菌浓度的β-内酰胺类药物可以通过诱导 SarA 调控的 表达来加重 MRSA 感染的结果。
