Cellular adaptation and the importance of the purine biosynthesis pathway during biofilm formation in Gram-positive pathogens

Abstract

Bacterial biofilms are involved in chronic infections and confer 10 to 1000 times more resistance to antibiotics, leading to treatment failure and complications. When transitioning from a planktonic lifestyle to biofilms, certain Gram-positive bacteria are likely to modulate several cellular pathways including central carbon metabolism, primary biosynthesis pathways and production of secondary metabolites. These metabolic adaptations might play a crucial role in biofilm formation by Gram-positive pathogens such as Staphylococcus aureus and Enterococcus faecalis. Here, we performed a transcriptomic approach to identify cellular pathways that might be similarly regulated during biofilm formation in these bacteria. Different strains and biofilm-inducing media were used to identify a set of regulated genes that are common and independent of the environment or accessory genomes analysed. The gene set enrichment analysis of the transcriptome of four different strains of Gram-positive bacteria identified biosynthesis of secondary metabolites, biosynthesis of antibiotics and purine biosynthesis as three commonly upregulated pathways in biofilm. Our approach did not highlight downregulated pathways during biofilm formation that were common to S. aureus and E. faecalis. Of the three upregulated pathways, the de novo IMP biosynthesis pathway constitutes a promising target of cellular adaptation during biofilm formation. Gene deletions in this pathway, particularly purN, purL, purQ, purH and purM significantly impaired biofilm formation of S. aureus. ImportanceBiofilms are often involved in nosocomial infections and can cause serious chronic infections if not treated properly. Current anti-biofilm strategies rely on antibiotic usage, but they have a limited impact because of the biofilms intrinsic resistance to drugs. Metabolism remodelling likely plays a central role during biofilm formation, but it is still unclear if these cellular adaptations are shared between strains and species. Using comparative transcriptomics of different strains of Staphylococcus aureus and Enterococcus faecalis, we identified a core of commonly regulated genes during biofilm formation. Interestingly, we observed that the de novo IMP biosynthesis was systematically upregulated during biofilm formation. This pathway could constitute an interesting new anti-biofilm target to increase the host spectrum, drug efficiency and prevent resistance evolution. These results are also relevant to a better understanding of biofilm physiology.