Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
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DOI：
10.1371/journal.ppat.1000353
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发表时间：
2009-03
期刊：
影响因子：
6.7
通讯作者：
Oliver A
中科院分区：
文献类型：
--
作者：
Moya B;Dötsch A;Juan C;Blázquez J;Zamorano L;Haussler S;Oliver A
长期以来，青霉素结合蛋白(PBPs)的修饰降低其对β-内酰胺类抗生素的亲和力是革兰氏阳性球菌获得抗生素耐药性的一个重要机制(靶向修饰)。然而，在革兰氏阴性杆菌(GNR)中，这种机制被认为是不寻常的，并仅限于大多数物种的临床无关的实验室突变。以铜绿假单胞菌为模型，在全球住院患者中引起危及生命的感染的病原菌名单上名列前茅，我们表明多溴联苯并肺炎杆菌也可能在肾炎耐药的β-内酰胺类药物中发挥主要作用，但通过完全不同的机制。通过详细的遗传学研究，包括全基因组分析方法，我们证明了在体外、体内和临床环境中，高水平的(临床)β-内酰胺类耐药是由DacB编码的非必需的PBP4失活驱动的，它是β-内酰胺类药物的陷阱靶标。这种PBP的失活决定了高效和复杂的β-内酰胺类耐药反应，触发了染色体β-内酰胺酶AmpC的过度生产和CreBC(BlAB)双组分调节因子的特异性激活，这反过来在耐药中发挥了重要作用。这些发现是我们在理解β-内酰胺耐药生物学方面向前迈出的重要一步，更重要的是，它们为治疗传染病的潜在抗生素靶点开辟了新的视角。在他们被发现几十年后，β-内酰胺类药物仍然是我们用于治疗传染病的抗菌药的关键成分。然而，对这些抗生素的抗药性正在令人担忧地增加。细菌对β-内酰胺类抗生素产生耐药性有两种主要策略：产生使它们失活的酶(β-内酰胺酶)，或修改它们在细胞壁中的靶标(基本的青霉素结合蛋白，PBPS)。以铜绿假单胞菌为模型微生物，我们发现在体外和体内，高水平的(临床)β-内酰胺类耐药通常是通过一种先前未知的、完全不同的耐药途径发生的，这种耐药途径是由作为β-内酰胺类药物陷阱靶标的非必需PBP(PbP4)突变失活驱动的。我们发现，这种PBP的突变决定了高效和复杂的β-内酰胺类耐药反应，触发了染色体β-内酰胺酶AmpC的过度生产和双组分调节因子的特异性激活，这反过来在耐药中发挥了关键作用。这些发现是我们在理解β-内酰胺耐药生物学方面向前迈出的重要一步，更重要的是，它们为治疗传染病的潜在抗生素靶点开辟了新的视角。
It has long been recognized that the modification of penicillin-binding proteins (PBPs) to reduce their affinity for β-lactams is an important mechanism (target modification) by which Gram-positive cocci acquire antibiotic resistance. Among Gram-negative rods (GNR), however, this mechanism has been considered unusual, and restricted to clinically irrelevant laboratory mutants for most species. Using as a model Pseudomonas aeruginosa, high up on the list of pathogens causing life-threatening infections in hospitalized patients worldwide, we show that PBPs may also play a major role in β-lactam resistance in GNR, but through a totally distinct mechanism. Through a detailed genetic investigation, including whole-genome analysis approaches, we demonstrate that high-level (clinical) β-lactam resistance in vitro, in vivo, and in the clinical setting is driven by the inactivation of the dacB-encoded nonessential PBP4, which behaves as a trap target for β-lactams. The inactivation of this PBP is shown to determine a highly efficient and complex β-lactam resistance response, triggering overproduction of the chromosomal β-lactamase AmpC and the specific activation of the CreBC (BlrAB) two-component regulator, which in turn plays a major role in resistance. These findings are a major step forward in our understanding of β-lactam resistance biology, and, more importantly, they open up new perspectives on potential antibiotic targets for the treatment of infectious diseases. Decades after their discovery, β-lactams remain key components of our antimicrobial armamentarium for the treatment of infectious diseases. Nevertheless, resistance to these antibiotics is increasing alarmingly. There are two major bacterial strategies to develop resistance to β-lactam antibiotics: the production of enzymes that inactivate them (β-lactamases), or the modification of their targets in the cell wall (the essential penicillin-binding proteins, PBPs). Using the pathogen Pseudomonas aeruginosa as a model microorganism, we show that high-level (clinical) β-lactam resistance in vitro and in vivo frequently occurs through a previously unrecognized, totally distinct resistance pathway, driven by the mutational inactivation of a nonessential PBP (PBP4) that behaves as a trap target for β-lactams. We show that mutation of this PBP determines a highly efficient and complex β-lactam resistance response, triggering overproduction of the chromosomal β-lactamase AmpC and the specific activation of a two-component regulator, which in turn plays a key role in resistance. These findings are a major step forward in our understanding of β-lactam resistance biology, and, more importantly, they open up new perspectives on potential antibiotic targets for the treatment of infectious diseases.
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