title: The resistance of the yeast Saccharomyces cerevisiae to the biocide polyhexamethylene biguanide: involvement of cell wall integrity pathway and emerging role for YAP1.
abstract: BACKGROUND
  Polyhexamethylene biguanide (PHMB) is an antiseptic polymer that is mainly used for cleaning hospitals and pools and combating Acantamoeba infection. Its fungicide activity was recently shown by its lethal effect on yeasts that contaminate the industrial ethanol process, and on the PE-2 strain of Saccharomyces cerevisiae, one of the main fermenting yeasts in Brazil. This pointed to the need to know the molecular mechanism that lay behind the cell resistance to this compound. In this study, we examined the factors involved in PHMB-cell interaction and the mechanisms that respond to the damage caused by this interaction. To achieve this, two research strategies were employed: the expression of some genes by RT-qPCR and the analysis of mutant strains.
  
  
  RESULTS
  Cell Wall integrity (CWI) genes were induced in the PHMB-resistant Saccharomyces cerevisiae strain JP-1, although they are poorly expressed in the PHMB-sensitive Saccharomyces cerevisiae PE2 strain. This suggested that PHMB damages the glucan structure on the yeast cell wall. It was also confirmed by the observed sensitivity of the yeast deletion strains, Δslg1, Δrom2, Δmkk2, Δslt2, Δknr4, Δswi4 and Δswi4, which showed that the protein kinase C (PKC) regulatory mechanism is involved in the response and resistance to PHMB. The sensitivity of the Δhog1 mutant was also observed. Furthermore, the cytotoxicity assay and gene expression analysis showed that the part played by YAP1 and CTT1 genes in cell resistance to PHMB is unrelated to oxidative stress response. Thus, we suggested that Yap1p can play a role in cell wall maintenance by controlling the expression of the CWI genes.
  
  
  CONCLUSIONS
  The PHMB treatment of the yeast cells activates the PKC1/Slt2 (CWI) pathway. In addition, it is suggested that HOG1 and YAP1 can play a role in the regulation of CWI genes.
authors.affiliation: Interdepartmental Research Group in Metabolic Engineering, Av, Moraes Rego, 1235, Cidade Universitária, 50670-901, Recife, PE, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Elsztein
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: de Lucena
authors.forename: Marcos A
authors.initials: MA
authors.lastname: de Morais
mesh_terms: D001645:Biguanides / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism; D004202:Disinfectants / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000502:physiology*; D015870:Gene Expression; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001645:Biguanides; D004202:Disinfectants; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; C031233:polihexanide