Antimicrobial resistance to ceftazidime involving loss of penicillin-binding protein 3 in Burkholderia pseudomallei
Antimicrobial resistance to ceftazidime involving loss of penicillin-binding protein 3 in Burkholderia pseudomallei
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DOI：
10.1073/pnas.1111020108
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发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Peacock, Sharon J.
中科院分区：
文献类型：
--
作者：
Chantratita, Narisara;Rholl, Drew A.;Peacock, Sharon J.
已知的β-内酰胺类抗生素耐药机制包括β-内酰胺酶表达、药物靶点改变、细菌渗透性降低和药物外排增加。在这里，我们描述了一种独特的β-内酰胺耐药机制的生物威胁生物类鼻疽伯克霍尔德菌（类鼻疽的原因），与治疗失败，在长期头孢他啶治疗自然感染。对6名患者的初始头孢他啶敏感感染分离株和随后的头孢他啶耐药变异株的详细比较使我们确定了一种常见的大规模基因组丢失，涉及所有6种耐药菌株中至少49个基因。野生型B的突变分析。假鼻疽证明头孢他啶耐药性是由于基因组缺失区域内存在的编码青霉素结合蛋白3（BPSS 1219）的基因缺失。临床头孢他啶耐药变异体无法使用常用的实验室培养基（包括商业血液培养物）生长，使得这些变异体在诊断实验室中几乎无法检测到。众所周知，类鼻疽很难治愈，临床治疗失败在头孢他啶治疗的患者中很常见，头孢他啶是东南亚大部分地区的首选药物，其中大多数病例都有报道。此处描述的机制代表了头孢他啶治疗失败的解释，可能是一种常见但未检测到的耐药事件。
Known mechanisms of resistance to beta-lactam antibiotics include beta-lactamase expression, altered drug target, decreased bacterial permeability, and increased drug efflux. Here, we describe a unique mechanism of beta-lactam resistance in the biothreat organism Burkholderia pseudomallei (the cause of melioidosis), associated with treatment failure during prolonged ceftazidime therapy of natural infection. Detailed comparisons of the initial ceftazidime-susceptible infecting isolate and subsequent ceftazidime-resistant variants from six patients led us to identify a common, large-scale genomic loss involving a minimum of 49 genes in all six resistant strains. Mutational analysis of wild-type B. pseudomallei demonstrated that ceftazidime resistance was due to deletion of a gene encoding a penicillin-binding protein 3 (BPSS1219) present within the region of genomic loss. The clinical ceftazidime-resistant variants failed to grow using commonly used laboratory culture media, including commercial blood cultures, rendering the variants almost undetectable in the diagnostic laboratory. Melioidosis is notoriously difficult to cure and clinical treatment failure is common in patients treated with ceftazidime, the drug of first choice across most of Southeast Asia where the majority of cases are reported. The mechanism described here represents an explanation for ceftazidime treatment failure, and may be a frequent but undetected resistance event.