Defining the architecture of KPC-2 Carbapenemase: identifying allosteric networks to fight antibiotics resistance.
Defining the architecture of KPC-2 Carbapenemase: identifying allosteric networks to fight antibiotics resistance.
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DOI：
10.1038/s41598-018-31176-0
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发表时间：
2018-08-27
影响因子：
4.6
通讯作者：
Haider S
中科院分区：
文献类型：
--
作者：
Galdadas I;Lovera S;Pérez-Hernández G;Barnes MD;Healy J;Afsharikho H;Woodford N;Bonomo RA;Gervasio FL;Haider S
细菌病原体的多重耐药性的上升是医学科学面临的重大挑战之一。一个主要的担忧是β-内酰胺酶介导的耐药性在革兰氏阴性菌中的发展速度，从而危及最近批准的抗生素和抑制剂的疗效，分别包括碳青霉烯类和阿维巴坦。迫切需要新的策略来克服耐药性，这最终将通过更深入地了解β内酰胺酶的功能机制来促进，例如肺炎克雷伯菌碳青霉烯酶(KPC)。利用改进的采样计算方法和定点突变，我们报告了KPC-2酶中两个“疏水网络”的鉴定，它们的完整性被发现对蛋白质的稳定性和相应的耐药性是必不可少的。这些网络存在于整个结构中，负责结构的完整性和变构信号。网络的破坏导致kpc-2介导的耐药表型的丧失，导致对包括碳青霉烯类和头孢菌素在内的不同类别的β-内酰胺类抗生素的恢复敏感性。在A类β-内酰胺酶中发现“疏水网络”高度保守，这意味着它们适合作为治疗干预的潜在靶点。
The rise of multi-drug resistance in bacterial pathogens is one of the grand challenges facing medical science. A major concern is the speed of development of β-lactamase-mediated resistance in Gram-negative species, thus putting at risk the efficacy of the most recently approved antibiotics and inhibitors, including carbapenems and avibactam, respectively. New strategies to overcome resistance are urgently required, which will ultimately be facilitated by a deeper understanding of the mechanisms that regulate the function of β-lactamases such as the Klebsiella Pneumoniae carbapenemases (KPCs). Using enhanced sampling computational methods together with site-directed mutagenesis, we report the identification of two “hydrophobic networks” in the KPC-2 enzyme, the integrity of which has been found to be essential for protein stability and corresponding resistance. Present throughout the structure, these networks are responsible for the structural integrity and allosteric signaling. Disruption of the networks leads to a loss of the KPC-2 mediated resistance phenotype, resulting in restored susceptibility to different classes of β-lactam antibiotics including carbapenems and cephalosporins. The ”hydrophobic networks” were found to be highly conserved among class-A β-lactamases, which implies their suitability for exploitation as a potential target for therapeutic intervention.
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