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Title

Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 for Staphylococcus aureus MRSA β-lactam resistance

Authors
Published in Communications biology. 2019, vol. 2, 417
Abstract Staphylococcus aureus is a major human pathogen and represents a clinical challenge because of widespread antibiotic resistance. Methicillin resistant Staphylococcus aureus (MRSA) is particularly problematic and originates by the horizontal acquisition of mecA encoding PBP2a, an extracellular membrane anchored transpeptidase, which confers resistance to β-lactam antibiotics by allosteric gating of its active site channel. Herein, we show that dual disruption of PrsA, a lipoprotein chaperone displaying anti-aggregation activity, together with HtrA1, a membrane anchored chaperone/serine protease, resulted in severe and synergistic attenuation of PBP2a folding that restores sensitivity to β-lactams such as oxacillin. Purified PBP2a has a pronounced unfolding transition initiating at physiological temperatures that leads to irreversible precipitation and complete loss of activity. The concordance of genetic and biochemical data highlights the necessity for extracellular protein folding factors governing MRSA β-lactam resistance. Targeting the PBP2a folding pathway represents a particularly attractive adjuvant strategy to combat antibiotic resistance.
Keywords Anti-Bacterial Agents/pharmacologyBacterial Proteins/chemistry/genetics/metabolismHigh-Temperature Requirement A Serine Peptidase 1/genetics/metabolismHumansLipoproteins/genetics/metabolismMembrane Proteins/genetics/metabolismMethicillin-Resistant Staphylococcus aureus/drug effects/geneticsMicrobial Sensitivity TestsModelsMolecularPenicillin-Binding Proteins/chemistry/geneticsProtein ConformationStaphylococcal Infections/microbiologyStructure-Activity RelationshipBeta-Lactam Resistance
Identifiers
PMID: 31754647
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Structures
Research group Staphylococcus aureus: antibiotique résistance et signalisation (1030)
Projects
Swiss National Science Foundation: 310030_146540
Swiss National Science Foundation: 310030-146540; 310030-16611
Swiss National Science Foundation: 310030_169404
Citation
(ISO format)
ROCH, Mélanie et al. Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 for Staphylococcus aureus MRSA β-lactam resistance. In: Communications Biology, 2019, vol. 2, p. 417. doi: 10.1038/s42003-019-0667-0 https://archive-ouverte.unige.ch/unige:151784

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Deposited on : 2021-05-19

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