GplR1, an unusual TetR-like transcription factor in controls the production of cell wall glycopeptidolipids, colony morphology, and virulence.

is a major human pathogen, mostly infecting people with pre-existing lung conditions such as cystic fibrosis. The production of glycopeptidolipids (GPL) is a major determinant of virulence of this bacterium, with clinical isolates that lack GPL generally exhibiting more aggressive clinical behavior. The current paradigm is that GPL production is abolished via irreversible, spontaneous mutations taking place as part of in-host evolution. Little is known about the mechanisms or extent to which GPL production may be regulated. Here we describe an unusual TetR-like transcription factor of MAB_1638, that appears to be a strong positive regulator of the entire GPL biosynthesis and export gene cluster through a combination of direct and indirect mechanisms. The inactivation of abolished GPL production and thus led to stable rough colony morphology, as well as increased virulence in infection models, characteristic of rough, non-GPL-producers. Transcriptome analysis found the mutant had 118 differentially expressed genes, including the GPL locus and a second, recently described GPL-like locus that produces a related glycosylated lipopeptide called GP8L. Chromatin Immunoprecipitation and sequencing revealed a consensus inverted-repeat DNA sequence motif characteristic of genes regulated by Together, appears to encode a transcription factor required for production of GPL and therefore having a profound effect on virulence traits. We propose naming this gene (). This finding raises the important possibility that strains appearing smooth in laboratory growth conditions may nonetheless downregulate GPL-cluster genes in other conditions, including in-patient conditions, and thus acquire the phenotypic characteristics of rough strains.