title: Lesions in teichoic acid biosynthesis in Staphylococcus aureus lead to a lethal gain of function in the otherwise dispensable pathway.
abstract: An extensive study of teichoic acid biosynthesis in the model organism Bacillus subtilis has established teichoic acid polymers as essential components of the gram-positive cell wall. However, similar studies pertaining to therapeutically relevant organisms, such as Staphylococcus aureus, are scarce. In this study we have carried out a meticulous examination of the dispensability of teichoic acid biosynthetic enzymes in S. aureus. By use of an allelic replacement methodology, we examined all facets of teichoic acid assembly, including intracellular polymer production and export. Using this approach we confirmed that the first-acting enzyme (TarO) was dispensable for growth, in contrast to dispensability studies in B. subtilis. Upon further characterization, we demonstrated that later-acting gene products (TarB, TarD, TarF, TarIJ, and TarH) responsible for polymer formation and export were essential for viability. We resolved this paradox by demonstrating that all of the apparently indispensable genes became dispensable in a tarO null genetic background. This work suggests a lethal gain-of-function mechanism where lesions beyond the initial step in wall teichoic acid biosynthesis render S. aureus nonviable. This discovery poses questions regarding the conventional understanding of essential gene sets, garnered through single-gene knockout experiments in bacteria and higher organisms, and points to a novel drug development strategy targeting late steps in teichoic acid synthesis for the infectious pathogen S. aureus.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Health Science Centre 4H32, 1200 Main St., W. Hamilton, ON L8N 3Z5, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: D'Elia
authors.forename: Mark P
authors.initials: MP
authors.lastname: Pereira
authors.forename: Yu Seon
authors.initials: YS
authors.lastname: Chung
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhao
authors.forename: Andrew
authors.initials: A
authors.lastname: Chau
authors.forename: Teresa J
authors.initials: TJ
authors.lastname: Kenney
authors.forename: Mark C
authors.initials: MC
authors.lastname: Sulavik
authors.forename: Todd A
authors.initials: TA
authors.lastname: Black
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D005798:Genes, Bacterial / Q000502:physiology*; D010957:Plasmids; D013211:Staphylococcus aureus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D013682:Teichoic Acids / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D013682:Teichoic Acids; D017855:Transferases (Other Substituted Phosphate Groups); C023222:UDPacetylglucosamine-dolichyl-phosphate acetylglucosamine-1-phosphate transferase