Mutations upstream of fabI in triclosan resistant Staphylococcus aureus strains are associated with elevated fabI gene expression

Grandgirard, Denis; Furi, Leonardo; Ciusa, Maria Laura; Baldassarri, Lucilla; Knight, Daniel R; Morrissey, Ian; Largiadèr, Carlo Rodolfo; Leib, Stephen; Oggioni, Marco R (2015). Mutations upstream of fabI in triclosan resistant Staphylococcus aureus strains are associated with elevated fabI gene expression. BMC Genomics, 16(345), p. 345. BioMed Central 10.1186/s12864-015-1544-y

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Background The enoyl-acyl carrier protein (ACP) reductase enzyme (FabI) is the target for a series of antimicrobial agents including novel compounds in clinical trial and the biocide triclosan. Mutations in fabI and heterodiploidy for fabI have been shown to confer resistance in S. aureus strains in a previous study. Here we further determined the fabI upstream sequence of a selection of these strains and the gene expression levels in strains with promoter region mutations. Results Mutations in the fabI promoter were found in 18% of triclosan resistant clinical isolates, regardless the previously identified molecular mechanism conferring resistance. Although not significant, a higher rate of promoter mutations were found in strains without previously described mechanisms of resistance. Some of the mutations identified in the clinical isolates were also detected in a series of laboratory mutants. Microarray analysis of selected laboratory mutants with fabI promoter region mutations, grown in the absence of triclosan, revealed increased fabI expression in three out of four tested strains. In two of these strains, only few genes other than fabI were upregulated. Consistently with these data, whole genome sequencing of in vitro selected mutants identified only few mutations except the upstream and coding regions of fabI, with the promoter mutation as the most probable cause of fabI overexpression. Importantly the gene expression profiling of clinical isolates containing similar mutations in the fabI promoter also showed, when compared to unrelated non-mutated isolates, a significant up-regulation of fabI. Conclusions In conclusion, we have demonstrated the presence of C34T, T109G, and A101C mutations in the fabI promoter region of strains with fabI up-regulation, both in clinical isolates and/or laboratory mutants. These data provide further observations linking mutations upstream fabI with up-regulated expression of the fabI gene.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
04 Faculty of Medicine > Faculty Institutions > Teaching Staff, Faculty of Medicine
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research

UniBE Contributor:

Grandgirard, Denis; Largiadèr, Carlo Rodolfo and Leib, Stephen

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1471-2164

Publisher:

BioMed Central

Funders:

[UNSPECIFIED] EC project KBBE-227258 (BIOHYPO)
[UNSPECIFIED] ECCMID Study group for brain infections (ESGIB)

Projects:

[UNSPECIFIED] BIOHYPO

Language:

English

Submitter:

Stephen Leib

Date Deposited:

19 May 2015 14:54

Last Modified:

26 Jun 2016 02:02

Publisher DOI:

10.1186/s12864-015-1544-y

PubMed ID:

25924916

Uncontrolled Keywords:

Biocide; Resistance; Triclosan; fabI ; Microarray; Cross-resistance; Promoter mutation

BORIS DOI:

10.7892/boris.68458

URI:

https://boris.unibe.ch/id/eprint/68458

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