Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to β-lactam Antibiotics.
Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to β-lactam Antibiotics.
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DOI：
10.1016/j.ebiom.2016.05.041
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发表时间：
2016-07
期刊：
影响因子：
11.1
通讯作者：
Pym AS
中科院分区：
文献类型：
--
作者：
Cohen KA;El-Hay T;Wyres KL;Weissbrod O;Munsamy V;Yanover C;Aharonov R;Shaham O;Conway TC;Goldschmidt Y;Bishai WR;Pym AS
结核分枝杆菌（M.结核病）被认为对β-内酰胺抗生素具有先天耐药性。然而，有证据表明，临床分离株对β-内酰胺类抗生素联合β-内酰胺酶抑制剂的敏感性各不相同，这些可能为耐药病例提供治疗选择。在这里，我们报告我们的调查敏感性β-内酰胺/β-内酰胺酶抑制剂组合之间的临床分离的M。结核病，并使用比较基因组学来了解观察到的易感性异质性。89株不同一线和二线药物敏感模式的南非临床分离株和两株M.结核杆菌对两种β-内酰胺类抗生素阿莫西林和美罗培南单用及与β-内酰胺酶抑制剂克拉维汀联用的最低抑菌浓度（MIC）测定。相对于参考菌株，发现41/91（45%）的测试分离株对阿莫西林/克拉维酸高敏感，包括14/24（58%）的多重耐药（MDR）和22/38（58%）的广泛耐药（XDR）分离株。采用全基因组测序鉴定的全基因组多态性用于遗传学感知线性混合模型，以鉴定与阿莫西林/克拉维汀敏感性相关的多态性。阿莫西林/克拉维霉素的敏感性在特定分支（LAM 4）的分离株中，特别是在XDR菌株中过度代表。12组多态性被确定为阿莫西林/克拉维汀敏感性的推定标记，其中5个仅限于LAM 4。在LAM4进化枝中，对阿莫西林/克拉维酸的"矛盾过敏性"与一线和二线耐药平行进化。鉴于南非广泛耐药结核病中LAM 4的高患病率，我们的数据支持β-内酰胺/β-内酰胺酶抑制剂组合在治疗耐药结核分枝杆菌中的作用扩大。结核特异性过敏是观察到的药物敏感性，尽管在野生型状态下存在先天抗性。许多MDR和XDR M。结核菌株对阿莫西林/克拉维酸敏感。全基因组测序鉴定了与反常过敏性相关的突变。β-内酰胺类药物在耐药M.结核病得到支持。全球耐药结核病的增加促使人们寻找替代疗法，包括重新利用现有的抗生素。β-内酰胺抗生素是安全的药物，然而，由于对这类药物的先天耐药性，它们以前被认为对结核病的使用有限。在这项研究中，作者发现许多来自南非的耐药结核病分离株对β-内酰胺和β-内酰胺酶组合阿莫西林/克拉维酸敏感。利用比较基因组学，多个基因突变被确定为与这种过敏表型。这些发现支持β-内酰胺/β-内酰胺酶抑制剂组合在治疗耐药结核病中的扩展作用。
Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis. Paradoxical hypersusceptibility is observed drug susceptibility despite innate resistance in the wild type state. Many MDR and XDR M. tuberculosis strains are susceptible to amoxicillin/clavulanate. Whole-genome sequencing identified mutations associated with paradoxical hypersusceptibility. An expanded role for β-lactams in drug-resistant M. tuberculosis is supported. The global increase in drug-resistant tuberculosis has prompted a search for alternative therapies, including repurposing existing antibiotics. β-lactam antibiotics are safe drugs, however, they have previously been thought to be of limited use for tuberculosis due to innate resistance to this drug class. In this study, the authors found many drug-resistant tuberculosis isolates from South Africa to be susceptible to a β-lactam and β-lactamase combination, amoxicillin/clavulanate. With the use of comparative genomics, multiple genetic mutations were identified to be associated with this hypersusceptible phenotype. These findings support an expanded role of β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant TB.