title: Understanding the Structure-Function Relationship of Lysozyme Resistance in Staphylococcus aureus by Peptidoglycan O-Acetylation Using Molecular Docking, Dynamics, and Lysis Assay.
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.
authors.forename: Anju C
authors.initials: AC
authors.lastname: Pushkaran
authors.forename: Namrata
authors.initials: N
authors.lastname: Nataraj
authors.forename: Nisha
authors.initials: N
authors.lastname: Nair
authors.affiliation: ‡Microbial Genetics, Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT), University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
authors.forename: Raja
authors.initials: R
authors.lastname: Biswas
authors.forename: C Gopi
authors.initials: CG
authors.lastname: Mohan
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D020134:Catalytic Domain; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009113:Muramidase / Q000378:metabolism / Q000494:pharmacology*; D009154:Mutation; D009844:Oligosaccharides / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000166:cytology* / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D009844:Oligosaccharides; D010457:Peptidoglycan; D000123:Acetyltransferases; D009113:Muramidase