The ClpX chaperone controls autolytic splitting of Staphylococcus aureus daughter cells, but is bypassed by β-lactam antibiotics or inhibitors of WTA biosynthesis


Autoři: Camilla Jensen aff001;  Kristoffer T. Bæk aff001;  Clement Gallay aff002;  Ida Thalsø-Madsen aff001;  Lijuan Xu aff001;  Ambre Jousselin aff003;  Fernando Ruiz Torrubia aff001;  Wilhelm Paulander aff001;  Ana R. Pereira aff003;  Jan-Willem Veening aff002;  Mariana G. Pinho aff003;  Dorte Frees aff001
Působiště autorů: Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark aff001;  Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland aff002;  Bacterial Cell Biology, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal aff003
Vyšlo v časopise: The ClpX chaperone controls autolytic splitting of Staphylococcus aureus daughter cells, but is bypassed by β-lactam antibiotics or inhibitors of WTA biosynthesis. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1008044
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008044

Souhrn

β-lactam antibiotics interfere with cross-linking of the bacterial cell wall, but the killing mechanism of this important class of antibiotics is not fully understood. Serendipitously we found that sub-lethal doses of β-lactams rescue growth and prevent spontaneous lysis of Staphylococcus aureus mutants lacking the widely conserved chaperone ClpX, and we reasoned that a better understanding of the clpX phenotypes could provide novel insights into the downstream effects of β-lactam binding to the PBP targets. Super-resolution imaging revealed that clpX cells display aberrant septum synthesis, and initiate daughter cell separation prior to septum completion at 30°C, but not at 37°C, demonstrating that ClpX becomes critical for coordinating the S. aureus cell cycle as the temperature decreases. FtsZ localization and dynamics were not affected in the absence of ClpX, suggesting that ClpX affects septum formation and autolytic activation downstream of Z-ring formation. Interestingly, oxacillin antagonized the septum progression defects of clpX cells and prevented lysis of prematurely splitting clpX cells. Strikingly, inhibitors of wall teichoic acid (WTA) biosynthesis that work synergistically with β-lactams to kill MRSA synthesis also rescued growth of the clpX mutant, as did genetic inactivation of the gene encoding the septal autolysin, Sle1. Taken together, our data support a model in which Sle1 causes premature splitting and lysis of clpX daughter cells unless Sle1-dependent lysis is antagonized by β-lactams or by inhibiting an early step in WTA biosynthesis. The finding that β-lactams and inhibitors of WTA biosynthesis specifically prevent lysis of a mutant with dysregulated autolytic activity lends support to the idea that PBPs and WTA biosynthesis play an important role in coordinating cell division with autolytic splitting of daughter cells, and that β-lactams do not kill S. aureus simply by weakening the cell wall.

Klíčová slova:

Biology and life sciences – Organisms – Bacteria – Staphylococcus – Staphylococcus aureus – Methicillin-resistant Staphylococcus aureus – Microbiology – Medical microbiology – Microbial pathogens – Bacterial pathogens – Microbial control – Antimicrobials – Antibiotics – Cell biology – Cell processes – Cell cycle and cell division – Cellular structures and organelles – Cell walls – Physiology – Physiological processes – Tissue repair – Lysis (medicine) – Biochemistry – Biosynthesis – Medicine and health sciences – Pathology and laboratory medicine – Pathogens – Pharmacology – Drugs – Physical sciences – Chemistry – Polymer chemistry – Macromolecules – Polymers – Peptidoglycans – Materials science – Materials


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