title: Revising the role of the pneumococcal vex-vncRS locus in vancomycin tolerance.
abstract: Vancomycin is used increasingly to treat invasive infections caused by multidrug-resistant Streptococcus pneumoniae. Although no vancomycin-resistant strains have been isolated to date, tolerant strains that fail to die rapidly and that cause relapsing disease have been described. The vex123-pep27-vncRS locus, consisting of an ABC transporter, a presumed signaling peptide, and a two-component system, respectively, has been implicated in vancomycin tolerance. Recent findings, however, challenged this model. The data presented here indicate that erythromycin in the growth medium induces a vancomycin-tolerant phenotype and that loss of function of Pep27 or VncRS does not alter autolysis. However, a role for the ABC transporter encoded by the vex123 genes in tolerance was confirmed. A vex3 mutant was considerably more tolerant to vancomycin treatment than the wild-type strain T4, and the strength of the phenotype depended on the orientation of the resistance cassette used to construct the mutant. Microarray results suggested a number of genes that might be involved in tolerance in the vex3 mutant. Although the exact function and regulation of the vex123-pep27-vncRS locus remains to be determined, several factors influence the autolysis behavior of S. pneumoniae, including the bacterial capsule, erythromycin, and the lytA and vex3 gene products.
authors.affiliation: Department of Infectious Diseases, 332 N. Lauderdale St., Memphis, TN 38105, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Haas
authors.forename: Jack
authors.initials: J
authors.lastname: Sublett
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001329:Autolysis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015169:Colony Count, Microbial; D003470:Culture Media; D004361:Drug Tolerance / Q000235:genetics*; D004917:Erythromycin / Q000494:pharmacology; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D020411:Oligonucleotide Array Sequence Analysis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D014157:Transcription Factors; C119633:VncR protein, Streptococcus pneumoniae; D004917:Erythromycin; D014640:Vancomycin; D011494:Protein Kinases; C119671:VncS histidine kinase