Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.

The continuous evolution of β-lactamases resulting in bacterial resistance to β-lactam antibiotics is a major concern in public health, and yet the underlying molecular basis or the pattern of such evolution is largely unknown. We investigated the mechanics of the substrate fspectrum expansion of th...

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Autores principales:	Hyojeong Yi, Kwang-Hwi Cho, Yun Sung Cho, Karan Kim, William C Nierman, Heenam Stanley Kim
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/47190b704b89498294471fc24515f106
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spelling	oai:doaj.org-article:47190b704b89498294471fc24515f1062021-11-18T07:17:48ZTwelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.1932-620310.1371/journal.pone.0037585https://doaj.org/article/47190b704b89498294471fc24515f1062012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22629423/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The continuous evolution of β-lactamases resulting in bacterial resistance to β-lactam antibiotics is a major concern in public health, and yet the underlying molecular basis or the pattern of such evolution is largely unknown. We investigated the mechanics of the substrate fspectrum expansion of the class A β-lactamase using PenA of Burkholderia thailandensis as a model. By analyzing 516 mutated enzymes that acquired the ceftazidime-hydrolyzing activity, we found twelve positions with single amino acid substitutions (altogether twenty-nine different substitutions), co-localized at the active-site pocket area. The ceftazidime MIC (minimum inhibitory concentration) levels and the relative frequency in the occurrence of substitutions did not correlate well with each other, and the latter appeared be largely influenced by the intrinsic mutational biases present in bacteria. Simulation studies suggested that all substitutions caused a congruent effect, expanding the space in a conserved structure called the omega loop, which in turn increased flexibility at the active site. A second phase of selection, in which the mutants were placed under increased antibiotic pressure, did not result in a second mutation in the coding region, but a mutation that increased gene expression arose in the promoter. This result suggests that the twelve amino acid positions and their specific substitutions in PenA may represent a comprehensive repertoire of the enzyme's adaptability to a new substrate. These mapped substitutions represent a comprehensive set of general mechanical paths to substrate spectrum expansion in class A β-lactamases that all share a functional evolutionary mechanism using common conserved residues.Hyojeong YiKwang-Hwi ChoYun Sung ChoKaran KimWilliam C NiermanHeenam Stanley KimPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e37585 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hyojeong Yi Kwang-Hwi Cho Yun Sung Cho Karan Kim William C Nierman Heenam Stanley Kim Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
description	The continuous evolution of β-lactamases resulting in bacterial resistance to β-lactam antibiotics is a major concern in public health, and yet the underlying molecular basis or the pattern of such evolution is largely unknown. We investigated the mechanics of the substrate fspectrum expansion of the class A β-lactamase using PenA of Burkholderia thailandensis as a model. By analyzing 516 mutated enzymes that acquired the ceftazidime-hydrolyzing activity, we found twelve positions with single amino acid substitutions (altogether twenty-nine different substitutions), co-localized at the active-site pocket area. The ceftazidime MIC (minimum inhibitory concentration) levels and the relative frequency in the occurrence of substitutions did not correlate well with each other, and the latter appeared be largely influenced by the intrinsic mutational biases present in bacteria. Simulation studies suggested that all substitutions caused a congruent effect, expanding the space in a conserved structure called the omega loop, which in turn increased flexibility at the active site. A second phase of selection, in which the mutants were placed under increased antibiotic pressure, did not result in a second mutation in the coding region, but a mutation that increased gene expression arose in the promoter. This result suggests that the twelve amino acid positions and their specific substitutions in PenA may represent a comprehensive repertoire of the enzyme's adaptability to a new substrate. These mapped substitutions represent a comprehensive set of general mechanical paths to substrate spectrum expansion in class A β-lactamases that all share a functional evolutionary mechanism using common conserved residues.
format	article
author	Hyojeong Yi Kwang-Hwi Cho Yun Sung Cho Karan Kim William C Nierman Heenam Stanley Kim
author_facet	Hyojeong Yi Kwang-Hwi Cho Yun Sung Cho Karan Kim William C Nierman Heenam Stanley Kim
author_sort	Hyojeong Yi
title	Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
title_short	Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
title_full	Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
title_fullStr	Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
title_full_unstemmed	Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
title_sort	twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/47190b704b89498294471fc24515f106
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Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.

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