Functional profiling of CHAP domain-containing peptidoglycan hydrolases of Staphylococcus aureus USA300 uncovers potential targets for anti-staphylococcal therapies

Min Wang, Xiaofang Li, Francis M. Cavallo, Harita Yedavally, Sjouke Piersma, Elisa J.M. Raineri, Elias Vera Murguia, Jeroen Kuipers, Zhenhua Zhang, Jan Maarten van Dijl*, Girbe Buist*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The bacterial pathogen Staphylococcus aureus employs a thick cell wall for protection against physical and chemical insults. This wall requires continuous maintenance to ensure strength and barrier integrity, but also to permit bacterial growth and division. The main cell wall component is peptidoglycan. Accordingly, the bacteria produce so-called peptidoglycan hydrolases (PGHs) that cleave glycan strands to facilitate growth, cell wall remodelling, separation of divided cells and release of exported proteins into the extracellular milieu. A special class of PGHs contains so-called ‘cysteine, histidine-dependent amidohydrolase/peptidase’ (CHAP) domains. In the present study, we profiled the roles of 11 CHAP PGHs encoded by the core genome of S. aureus USA300 LAC. Mutant strains lacking individual CHAP PGHs were analysed for growth, cell morphology, autolysis, and invasion and replication inside human lung epithelial cells. The results show that several investigated CHAP PGHs contribute to different extents to extracellular and intracellular growth and replication of S. aureus, septation of dividing cells, daughter cell separation once the division process is completed, autolysis and biofilm formation. In particular, the CHAP PGHs Sle1 and SAUSA300_2253 control intracellular staphylococcal replication and the resistance to β-lactam antibiotics like oxacillin. This makes the S. aureus PGHs in general, and the Sle1 and SAUSA300_2253 proteins in particular, attractive targets for future prophylactic or therapeutic anti-staphylococcal interventions. Alternatively, these cell surface-exposed enzymes, or particular domains of these enzymes, could be applied in innovative anti-staphylococcal therapies.

Original languageEnglish
Article number151632
Number of pages13
JournalInternational journal of medical microbiology
Volume316
DOIs
Publication statusPublished - Sept-2024

Keywords

  • CHAP-domain
  • Peptidoglycan hydrolase
  • PGH
  • Staphylococcus aureus

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