title: The Cell Wall Polymer Lipoteichoic Acid Becomes Nonessential in Staphylococcus aureus Cells Lacking the ClpX Chaperone.
abstract: Lipoteichoic acid (LTA) is an important cell wall component of Gram-positive bacteria and a promising target for the development of vaccines and antimicrobial compounds against Staphylococcus aureus Here we demonstrate that mutations in the conditionally essential ltaS (LTA synthase) gene arise spontaneously in an S. aureus mutant lacking the ClpX chaperone. A wide variety of ltaS mutations were selected, and among these, a substantial portion resulted in premature stop codons and other changes predicted to abolish LtaS synthesis. Consistent with this assumption, the clpX ltaS double mutants did not produce LTA, and genetic analyses confirmed that LTA becomes nonessential in the absence of the ClpX chaperone. In fact, inactivation of ltaS alleviated the severe growth defect conferred by the clpX deletion. Microscopic analyses showed that the absence of ClpX partly alleviates the septum placement defects of an LTA-depleted strain, while other phenotypes typical of LTA-negative S. aureus mutants, including increased cell size and decreased autolytic activity, are retained. In conclusion, our results indicate that LTA has an essential role in septum placement that can be bypassed by inactivating the ClpX chaperone.
  
  
  
  Lipoteichoic acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the lipoteichoic acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that lipoteichoic acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus.
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark df@sund.ku.dk ktb@sund.ku.dk.
authors: Kristoffer T
authors: KT
authors: Bæk
authors: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
authors: Lisa
authors: L
authors: Bowman
authors: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
authors: Charlotte
authors: C
authors: Millership
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors: Mia
authors: M
authors: Dupont Søgaard
authors: Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany.
authors: Volkhard
authors: V
authors: Kaever
authors: Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland Institute of Biotechnology, Proteomics Unit, University of Helsinki, Helsinki, Finland.
authors: Pia
authors: P
authors: Siljamäki
authors: Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors: Kirsi
authors: K
authors: Savijoki
authors: Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors: Pekka
authors: P
authors: Varmanen
authors: Institute of Biotechnology, Proteomics Unit, University of Helsinki, Helsinki, Finland.
authors: Tuula A
authors: TA
authors: Nyman
authors: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
authors: Angelika
authors: 0000-0002-6235-8687
authors: A
authors: Gründling
authors: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark df@sund.ku.dk ktb@sund.ku.dk.
authors: Dorte
authors: D
authors: Frees
mesh_terms: D049071:Endopeptidase Clp / Q000172:deficiency* / Q000378:metabolism*; D055786:Gene Knockout Techniques; D020043:Genes, Essential; D008025:Ligases / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D050296:Microbial Viability; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D013211:Staphylococcus aureus / Q000235:genetics / Q000254:growth & development / Q000502:physiology* / Q000648:ultrastructure; D013682:Teichoic Acids / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D013682:Teichoic Acids; C009900:lipoteichoic acid; D049071:Endopeptidase Clp; D008025:Ligases