Ji-Young Lee1, Eun Seon Chung1, In Young Na1, Hyunkeun Kim1, Dongwoo Shin1, Kwan Soo Ko2. 1. Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea. 2. Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea ksko@skku.edu.
Abstract
OBJECTIVES: Colistin susceptibility in Pseudomonas aeruginosa is associated with a lipopolysaccharide (LPS) structure that is controlled by the modulation of several two-component regulatory systems. In this study, we attempted to elucidate the role of these two-component systems in the development of colistin resistance in P. aeruginosa. METHODS: pmrA-, phoP-, parR- or cprR-inactivated mutants were constructed from a colistin-susceptible P5 strain. Colistin-resistant mutants (P5R, P5ΔpmrA-R, P5ΔphoP-R, P5ΔparR-R and P5ΔcprR-R) were developed in vitro from a wild-type strain (P5) and pmrA-, phoP-, parR- or cprR-inactivated mutants by serial passage in colistin-containing media. Expression levels of the pmrA, phoP, parR, cprR and arnB genes were determined and amino acid alterations of two-component regulatory systems during development of colistin resistance were also investigated. RESULTS: While P5ΔpmrA-R, P5ΔparR-R and P5ΔcprR-R showed elevated expression of the phoP gene, the expression levels of the pmrA, parR and cprR genes were not different between gene-inactivated mutants and the adapted colistin-resistant mutants. P5ΔphoP-R showed no significant elevation in expression of any of the pmrA, parR or cprR genes. The arnB gene was overexpressed in all in vitro-selected colistin-resistant mutants compared with colistin-susceptible wild-type and gene-inactivated mutants. Three amino acid alterations in PhoQ and three in ParS were identified in induced colistin-resistant mutants. CONCLUSIONS: Our data suggest that individual two-component systems may not be essential for the acquisition of colistin resistance in P. aeruginosa. The PhoPQ two-component system may play a major role in the development of colistin resistance in our strains, but alternative or compensatory pathways may exist.
OBJECTIVES: Colistin susceptibility in Pseudomonas aeruginosa is associated with a lipopolysaccharide (LPS) structure that is controlled by the modulation of several two-component regulatory systems. In this study, we attempted to elucidate the role of these two-component systems in the development of colistin resistance in P. aeruginosa. METHODS: pmrA-, phoP-, parR- or cprR-inactivated mutants were constructed from a colistin-susceptible P5 strain. Colistin-resistant mutants (P5R, P5ΔpmrA-R, P5ΔphoP-R, P5ΔparR-R and P5ΔcprR-R) were developed in vitro from a wild-type strain (P5) and pmrA-, phoP-, parR- or cprR-inactivated mutants by serial passage in colistin-containing media. Expression levels of the pmrA, phoP, parR, cprR and arnB genes were determined and amino acid alterations of two-component regulatory systems during development of colistin resistance were also investigated. RESULTS: While P5ΔpmrA-R, P5ΔparR-R and P5ΔcprR-R showed elevated expression of the phoP gene, the expression levels of the pmrA, parR and cprR genes were not different between gene-inactivated mutants and the adapted colistin-resistant mutants. P5ΔphoP-R showed no significant elevation in expression of any of the pmrA, parR or cprR genes. The arnB gene was overexpressed in all in vitro-selected colistin-resistant mutants compared with colistin-susceptible wild-type and gene-inactivated mutants. Three amino acid alterations in PhoQ and three in ParS were identified in induced colistin-resistant mutants. CONCLUSIONS: Our data suggest that individual two-component systems may not be essential for the acquisition of colistin resistance in P. aeruginosa. The PhoPQ two-component system may play a major role in the development of colistin resistance in our strains, but alternative or compensatory pathways may exist.
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