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One origin for metallo-β-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic trees

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Date
10/2014
Author
Alderson, Rosanna Grace
Barker, Daniel
Mitchell, John B. O.
Keywords
Metallo-β-lactamase
Antibiotic resistance
Phylogenetics
Most recent common ancestor
Ancestral sequence reconstruction
Exaptation
QH301 Biology
QD Chemistry
DAS
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Abstract
Bacteria use metallo-β-lactamase enzymes to hydrolyse lactam rings found in many antibiotics, rendering them ineffective. Metallo-β-lactamase activity is thought to be polyphyletic, having arisen on more than one occasion within a single functionally diverse homologous superfamily. Since discovery of multiple origins of enzymatic activity conferring antibiotic resistance has broad implications for the continued clinical use of antibiotics, we test the hypothesis of polyphyly further; if lactamase function has arisen twice independently, the most recent common ancestor (MRCA) is not expected to possess lactam-hydrolysing activity. Two major problems present themselves. Firstly, even with a perfectly known phylogeny, ancestral sequence reconstruction is error prone. Secondly, the phylogeny is not known, and in fact reconstructing a single, unambiguous phylogeny for the superfamily has proven impossible. To obtain a more statistical view of the strength of evidence for or against MRCA lactamase function, we reconstructed a sample of 98 MRCAs of the metallo-β-lactamases, each based on a different tree in a bootstrap sample of reconstructed phylogenies. InterPro sequence signatures and homology modelling were then used to assess our sample of MRCAs for lactamase functionality. Only 5 % of these models conform to our criteria for metallo-β-lactamase functionality, suggesting that the ancestor was unlikely to have been a metallo-β-lactamase. On the other hand, given that ancestral proteins may have had metallo-β-lactamase functionality with variation in sequence and structural properties compared with extant enzymes, our criteria are conservative, estimating a lower bound of evidence for metallo-β-lactamase functionality but not an upper bound.
Citation
Alderson , R G , Barker , D & Mitchell , J B O 2014 , ' One origin for metallo-β-lactamase activity, or two? An investigation assessing a diverse set of reconstructed ancestral sequences based on a sample of phylogenetic trees ' , Journal of Molecular Evolution , vol. 79 , no. 3-4 , pp. 117-129 . https://doi.org/10.1007/s00239-014-9639-7
Publication
Journal of Molecular Evolution
Status
Peer reviewed
DOI
https://doi.org/10.1007/s00239-014-9639-7
ISSN
0022-2844
Type
Journal article
Rights
© The Author(s) 2014. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Description
This work was supported by BBSRC (grant BB/F016778/1)
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/5331

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