Mucoid switch in Burkholderia cepacia complex bacteria: Triggers, molecular mechanisms and implications in pathogenesis.

Bacteria produce a vast range of exopolysaccharides (EPSs) to thrive in diverse environmental niches and often display a mucoid phenotype in solid media. One such exopolysaccharide, cepacian, is produced by bacteria of the genus Burkholderia and is of interest due to its role in pathogenesis associated with lung infections in cystic fibrosis (CF) patients. Cepacian is a repeat-unit polymer that has been implicated in biofilm formation, immune system evasion, interaction with host cells, resistance against antimicrobials, and virulence. Its biosynthesis proceeds through the Wzy-dependent polymerization and secretion mechanism, which requires a multienzymatic complex. Key aspects of its structure, genetic organization, and the regulatory network involved in mucoid switch and regulation of cepacian biosynthesis at transcriptional and posttranscriptional levels are reviewed. It is also evaluated the importance of cepacian biosynthesis/regulation key players as evolutionary targets of selection and highlighted the complexity of the regulatory network, which allows cells to coordinate the expression of metabolic functions to the ones of the cell wall, in order to be successful in ever changing environments, including in the interaction with host cells.

The OmpR Regulator of Burkholderia multivorans Controls Mucoid-to-Nonmucoid Transition and Other Cell Envelope Properties Associated with Persistence in the Cystic Fibrosis Lung.

Bacteria from the Burkholderia cepacia complex grow in different natural and man-made environments and are feared opportunistic pathogens that cause chronic respiratory infections in cystic fibrosis patients. Previous studies showed that Burkholderia mucoid clinical isolates grown under stress conditions give rise to nonmucoid variants devoid of the exopolysaccharide cepacian. Here, we determined that a major cause of the nonmucoid morphotype involves nonsynonymous mutations and small indels in the ompR gene encoding a response regulator of a two-component regulatory system. In trans complementation of nonmucoid variants (NMVs) with the native gene restored exopolysaccharide production. The loss of functional Burkholderia multivorans OmpR had positive effects on growth, adhesion to lung epithelial cells, and biofilm formation in high-osmolarity medium, as well as an increase in swimming and swarming motilities. In contrast, phenotypes such as antibiotic resistance, biofilm formation at low osmolarity, and virulence in Galleria mellonella were compromised by the absence of functional OmpR. Transcriptomic studies indicated that loss of the ompR gene affects the expression of 701 genes, many associated with outer membrane composition, motility, stress response, iron acquisition, and the uptake of nutrients, consistent with starvation tolerance. Since the stresses here imposed on B. multivorans may strongly resemble the ones found in the cystic fibrosis (CF) airways and mutations in the ompR gene from longitudinally collected CF isolates have been found, this regulator might be important for the production of NMVs in the CF environment.IMPORTANCE Within the cystic fibrosis (CF) lung, bacteria experience high-osmolarity conditions due to an ion unbalance resulting from defects in CF transmembrane conductance regulator (CFTR) protein activity in epithelial cells. Understanding how bacterial CF pathogens thrive in this environment might help the development of new therapeutic interventions to prevent chronic respiratory infections. Here, we show that the OmpR response regulator of one of the species found in CF respiratory infections, Burkholderia multivorans, is involved in the emergence of nonmucoid colony variants and is important for osmoadaptation by regulating several cell envelope components. Specifically, genetic, phenotypic, genomic, and transcriptomic approaches uncover OmpR as a regulator of cell wall remodeling under stress conditions, with implications in several phenotypes such as exopolysaccharide production, motility, antibiotic resistance, adhesion, and virulence.