Trans locus inhibitors limit concomitant polysaccharide synthesis in the human gut symbiont Bacteroides fragilis.

Bacteroides is an abundant genus of bacteria of the human intestinal microbiota. Bacteroides species synthesize a large number of capsular polysaccharides (PS), a biological property not shared with closely related oral species, suggesting importance for intestinal survival. Bacteroides fragilis, for example, synthesizes eight capsular polysaccharides per strain, each of which phase varies via inversion of the promoters located upstream of seven of the eight polysaccharide biosynthesis operons. In a single cell, many of these polysaccharide loci promoters can be simultaneously oriented on for transcription of the downstream biosynthesis operons. Here, we demonstrate that despite the promoter orientations, concomitant transcription of multiple polysaccharide loci within a cell is inhibited. The proteins encoded by the second gene of each of these eight loci, collectively designated the UpxZ proteins, inhibit the synthesis of heterologous polysaccharides. These unique proteins interfere with the ability of UpxY proteins encoded by other polysaccharide loci to function in transcriptional antitermination of their respective operon. The eight UpxZs have different inhibitory spectra, thus establishing a hierarchical regulatory network for polysaccharide synthesis. Limitation of concurrent polysaccharide synthesis strongly suggests that these bacteria evolved this property as an evasion-type mechanism to avoid killing by polysaccharide-targeting factors in the ecosystem.