Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL)

IF 1.4 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Anirudha Dutta, Antarika Chowdhury, Parijat Roy, Priyanka Bhowmik
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引用次数: 0

Abstract

Bacterial antimicrobial resistance is a great public health threat worldwide, a situation that is much escalated by the rapid propagation of Extended Spectrum β-lactamase (ESBL) enzymes. These can hydrolyze and inactivate a broad range of β-lactams, including third-generation cephalosporins, penicillin, and aztreonam and are known to be associated with various bacterial infections, ranging from uncomplicated urinary tract infections to life-threatening sepsis.Variation is the essential raw material of Darwinian evolution and the accumulation of mutations plays one of the most important roles in it. Sequential acquisition of spontaneous mutations followed by successive rounds of selection can be attributed as one of the major reasons for the rapid diversification of ESBL enzymes. The ESBLs are excellent examples of ‘microevolution’ that led to ‘gain-of-function’ with an extended substrate spectrum. However, acquiring newer phenotypes sometimes comes with fitness costs and different mutational pathways interact with each other, triggering both additive and non-additive fitness to generate a rugged fitness landscape, that influences the path a strain must follow to adapt and evolve under selection pressure. Therefore, it is important to understand the role of mutations in the emergence of these enzyme variants. This review focuses on the understanding of different facades of mutational pathways that lead to the adaptive evolution of ESBL phenotype. The structural and mechanistic basis of the extension of the substrate spectrum by mutations are also discussed.

突变对扩展谱β-内酰胺酶(ESBL)进化的影响。
细菌抗微生物药物耐药性是世界范围内重大的公共卫生威胁,这种情况因扩展谱β-内酰胺酶(ESBL)酶的快速传播而大大升级。它们可以水解和灭活多种β-内酰胺,包括第三代头孢菌素、青霉素和氨曲南,已知与各种细菌感染有关,从无并发症的尿路感染到危及生命的败血症。变异是达尔文进化论的基本原料,而突变的积累在其中起着重要的作用。自发突变的连续获得以及随后的连续几轮选择可以被认为是ESBL酶快速多样化的主要原因之一。ESBLs是“微进化”的极好例子,它导致了扩展底物光谱的“功能获得”。然而,获得新的表型有时伴随着适应度成本,不同的突变途径相互作用,触发加性和非加性适应度,从而产生崎岖的适应度景观,这影响了菌株在选择压力下适应和进化所必须遵循的路径。因此,了解突变在这些酶变体出现中的作用是很重要的。这篇综述的重点是对导致ESBL表型适应性进化的不同突变途径的理解。讨论了突变扩展底物光谱的结构和机理基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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