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Chemometric Analysis of Bacterial Peptidoglycan Reveals Atypical Modifications That Empower the Cell Wall against Predatory Enzymes and Fly Innate Immunity
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 29, p. 9193-9204Article in journal (Refereed) Published
Abstract [en]

Peptidoglycan is a fundamental structure for most bacteria. It contributes to the cell morphology and provides cell wall integrity against environmental insults. While several studies have reported a significant degree of variability in the chemical composition and organization of peptidoglycan in the domain Bacteria, the real diversity of this polymer is far from fully explored. This work exploits rapid ultraperformance liquid chromatography and multivariate data analysis to uncover peptidoglycan chemical diversity in the Class Alphaproteobacteria, a group of Gram negative bacteria that are highly heterogeneous in terms of metabolism, morphology and life-styles. Indeed, chemometric analyses revealed novel peptidoglycan structures conserved in Acetobacteria: amidation at the alpha-(L)-carboxyl of meso-diaminopimelic acid and the presence of muropeptides cross-linked by (1-3) L-Ala-D-(meso)diaminopimelate cross-links. Both structures are growth-controlled modifications that influence sensitivity to Type VI secretion system peptidoglycan endopeptidases and recognition by the Drosophila innate immune system, suggesting relevant roles in the environmental adaptability of these bacteria. Collectively our findings demonstrate the discriminative power of chemometric tools on large cell wall-chromatographic data sets to discover novel peptidoglycan structural properties in bacteria.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 138, no 29, p. 9193-9204
National Category
Chemical Sciences Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-125551DOI: 10.1021/jacs.6b04430ISI: 000380730000039PubMedID: 27337563OAI: oai:DiVA.org:umu-125551DiVA, id: diva2:971414
Available from: 2016-09-16 Created: 2016-09-13 Last updated: 2019-03-28Bibliographically approved
In thesis
1. Uncovering novel cell wall chemistries in gram negative bacteria: from development or dedicated peptidoglycan chemometric tools to functional genomics
Open this publication in new window or tab >>Uncovering novel cell wall chemistries in gram negative bacteria: from development or dedicated peptidoglycan chemometric tools to functional genomics
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacteria are surrounded by an external cell wall whose main component is a polymeric net-like structure called the peptidoglycan (PG) or murein sacculus. PG plays crucial roles in bacterial physiology (eg morphogenesis, growth fitness and regulation of innate immunity). Based on the characteristics of this macromolecule, bacteria are grouped as gram negative and positive. Gram negatives present a thin PG layer in the periplasmic space, while Gram positive bacteria contain one thick multi-layered sacculus covering the cytoplasmic membrane. Although the PG sacculus is widely conserved between bacteria, variations in its chemical structure (ie sugars and peptide components) have been reported as a coping mechanism to stress. For example, V. choleraeis able to downregulate PG biosynthesis through non-canonical D-amino acids (NCDAAs) cell wall editing when entering stationary phase. NCDAAs production relies on Bsr enzymes, broad spectrum racemases which are expressed in V. cholerae under the control of stress sigma factor RpoS. In this thesis, we present a comprehensive study that allows us to determine the basic structural and biochemical features required for prominent D-amino acid production by Bsr enzymes.

V. cholerae’s PG editing by NCDAAs revealed the existence of previously unappreciated  chemical modification in the cell wall of bacteria. Such an observation made us question whether the latest technology could reveal, otherwise undetectable, novel PG traits and furthermore, revisit the existence of murein in bacteria which were previously defined as PG-less. Finally, these studies would promote a global assessment of the degree of PG-chemical variability at a Kingdom scale.

On the search for novel functional chemistries and associated mechanisms of cell wall regulation, we analysed the cell wall of hundreds of different species. Here, I present two proof of concept studies: i) investigation of the existence of PG in the Plantomycetes Kuenenia stuttgartiensis, a species previously classified as PG-less; and ii) PG chemical diversity within Class Alphaproteobacteria. To do so, we developed and experimentally validated an innovative chemometric pipeline to rapidly analyse large PG datasets. Chemometric analyses revealed 3 PG clusters within Alphaproteobacteria, which included unprecedented PG modifications widely conserved in family Acetobacteria: amidation at the α-(L)-carboxyl of meso-diaminopimelic acid and the presence of (1–3) cross-linked muropeptides between L-Ala and D-(meso)-diaminopimelate residues from adjacent moieties. Fluctuations of the relative abundance of these PG traits were growth phase and media composition dependent. Functional studies demonstrated that Acetobacteria atypical muropeptides enabled cellular protection against Type VI secreted endopeptidases and negatively affected innate immune system recognition suggesting relevant functional roles in the environmental adaptability of these bacteria.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2019. p. 63
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2027
Keywords
Bacteria, cell wall, peptidoglycan, peptidoglycan variations, D-amino acids
National Category
Microbiology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-157645 (URN)978-91-7855-045-6 (ISBN)
Public defence
2019-04-26, Hörsal d Unod T 9, Umeå University Hospital, Umeå, 09:00 (English)
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Supervisors
Available from: 2019-04-05 Created: 2019-03-28 Last updated: 2019-04-05Bibliographically approved

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Espaillat, AkbarForsmo, OskarBjörk, RafaelTrygg, JohanCava, Felipe

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