Understanding the structure-function relationship of lysozyme resistance in Staphylococcus aureus by peptidoglycan o-acetylation using molecular docking, dynamics, and lysis assay

Anju C. Pushkaran, Namrata Nataraj, Nisha Nair, Friedrich Götz, Raja Biswas, C. Gopi Mohan

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Lysozyme is an important component of the host innate defense system. It cleaves the β-1,4 glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine of bacterial peptidoglycan and induce bacterial lysis. Staphylococcus aureus (S. aureus), an opportunistic commensal pathogen, is highly resistant to lysozyme, because of the O-acetylation of peptidoglycan by O-acetyl transferase (oatA). To understand the structure-function relationship of lysozyme resistance in S. aureus by peptidoglycan O-acetylation, we adapted an integrated approach to (i) understand the effect of lysozyme on the growth of S. aureus parental and the oatA mutant strain, (ii) study the lysozyme induced lysis of exponentially grown and stationary phase of both the S. aureus parental and oatA mutant strain, (iii) investigate the dynamic interaction mechanism between normal (de-O-acetylated) and O-acetylated peptidoglycan substrate in complex with lysozyme using molecular docking and molecular dynamics simulations, and (iv) quantify lysozyme resistance of S. aureus parental and the oatA mutant in different human biological fluids. The results indicated for the first time that the active site cleft of lysozyme binding with O-acetylated peptidoglycan in S. aureus was sterically hindered and the structural stability was higher for the lysozyme in complex with normal peptidoglycan. This could have conferred reduced survival of the S. aureus oatA mutant in different human biological fluids. Consistent with this computational analysis, the experimental data confirmed decrease in the growth, lysozyme induced lysis, and lysozyme resistance, due to peptidoglycan O-acetylation in S. aureus.

Original languageEnglish (US)
Pages (from-to)760-770
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume55
Issue number4
DOIs
StatePublished - Apr 27 2015

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Acetylation
Peptidoglycan
Muramidase
Assays
Enzymes
Transferases
simulation
interaction
Fluids
Acetylglucosamine
Pathogens
Molecular dynamics

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Understanding the structure-function relationship of lysozyme resistance in Staphylococcus aureus by peptidoglycan o-acetylation using molecular docking, dynamics, and lysis assay. / Pushkaran, Anju C.; Nataraj, Namrata; Nair, Nisha; Götz, Friedrich; Biswas, Raja; Mohan, C. Gopi.

In: Journal of Chemical Information and Modeling, Vol. 55, No. 4, 27.04.2015, p. 760-770.

Research output: Contribution to journalArticle

Pushkaran, Anju C. ; Nataraj, Namrata ; Nair, Nisha ; Götz, Friedrich ; Biswas, Raja ; Mohan, C. Gopi. / Understanding the structure-function relationship of lysozyme resistance in Staphylococcus aureus by peptidoglycan o-acetylation using molecular docking, dynamics, and lysis assay. In: Journal of Chemical Information and Modeling. 2015 ; Vol. 55, No. 4. pp. 760-770.
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AU - Götz, Friedrich

AU - Biswas, Raja

AU - Mohan, C. Gopi

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AB - Lysozyme is an important component of the host innate defense system. It cleaves the β-1,4 glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine of bacterial peptidoglycan and induce bacterial lysis. Staphylococcus aureus (S. aureus), an opportunistic commensal pathogen, is highly resistant to lysozyme, because of the O-acetylation of peptidoglycan by O-acetyl transferase (oatA). To understand the structure-function relationship of lysozyme resistance in S. aureus by peptidoglycan O-acetylation, we adapted an integrated approach to (i) understand the effect of lysozyme on the growth of S. aureus parental and the oatA mutant strain, (ii) study the lysozyme induced lysis of exponentially grown and stationary phase of both the S. aureus parental and oatA mutant strain, (iii) investigate the dynamic interaction mechanism between normal (de-O-acetylated) and O-acetylated peptidoglycan substrate in complex with lysozyme using molecular docking and molecular dynamics simulations, and (iv) quantify lysozyme resistance of S. aureus parental and the oatA mutant in different human biological fluids. The results indicated for the first time that the active site cleft of lysozyme binding with O-acetylated peptidoglycan in S. aureus was sterically hindered and the structural stability was higher for the lysozyme in complex with normal peptidoglycan. This could have conferred reduced survival of the S. aureus oatA mutant in different human biological fluids. Consistent with this computational analysis, the experimental data confirmed decrease in the growth, lysozyme induced lysis, and lysozyme resistance, due to peptidoglycan O-acetylation in S. aureus.

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