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New work from the Cava group provides novel insights into the genetics and physiology behind the peptidoglycan-recycling pathway

Media release Felipe SaraMost bacteria are surrounded by a protective cell wall consisting of a strong yet elastic polymer called peptidoglycan. The peptidoglycan cell wall is an essential structure for bacteria and thus, its biosynthesis and remodeling have always been in the spotlight when it comes to the development of antibiotics.

During bacterial growth, large amount of peptidoglycan fragments (also known as muropeptides) are released to the extracellular environment where they play roles in bacteria-bacteria and bacteria-host communication. However, in many species these fragments are predominantly re-internalized and recycled, a cellular process whose biological meaning has been elusive until now. 
Felipe Cava's research group at the Molecular Infection Medicine Sweden (MIMS) studied the genetics and physiology behind the peptidoglycan-recycling pathway using as experimental model the causative agent of cholera, Vibrio cholerae. The study was performed in collaboration with Tobias Dörr (Cornell University, USA) and Matthew K. Waldor (Harvard Medical School, USA) and the results have been published in the journal Cell Reports on 28th April.
The scientists have revealed an unnoticed link between PG recycling and synthesis to promote optimal cell wall assembly and composition.

The peptidoglycan recycling pathway is widely conserved amongst bacteria but its components are not essential and its roles in cell wall homeostasis were not well-understood. “Our lab found that the accumulation of an intermediate of the peptidoglycan recycling pathway modulates the synthesis and the degree of cross-linking of the cell wall; thus, our work provides new insights into the intersection between the PG recycling and the de novo synthesis pathways”, explained Felipe Cava, head of the study.
A critical step in peptidoglycan recycling is the transformation of peptidoglycan tetrapeptides into tripeptides by the cytosolic enzyme L,D-carboxypeptidase. We found that during stationary phase (i.e. growth arrest) V. cholerae produces non-canonical D-amino acids (NCDAA, e.g. D-Methionine) which generate changes in the normal chemical composition of the cell wall, explains Sara Hernández, postdoctoral researcher who conducted the study. “Muropeptides modified with NCDAA are poor substrates for LD-carboxypeptidases and hence, their recycling causes the accumulation of atypical tetrapeptide precursors which downregulate cell wall synthesis and crosslinking during stationary phase”, continues Sara Hernández.

Media release Felipe Sara summ fig

Figure by Sara B. Hernández et al.

Besides their role in regulating cell wall homeostasis, extracellular peptidoglycan fragments are known to be important signals in innate immunity, organ development and behavior. “Our observation that bacteria can release peptidoglycan fragments modified with NCDAA suggests that it will be important to consider whether NCDAA-modified peptidoglycan fragments convey distinct information in inter-kingdom signaling compared to fragments with canonical chemistries”, explained Felipe Cava, head of the study.
“Moreover, in microbial ecology, our findings suggest that release of extracellular non-canonical muropeptides could mediate interspecies peptidoglycan cross-regulation if such peptides become substrates for peptidoglycan recycling in neighboring organisms. Whether this regulation can promote cooperative or competitive behaviors is something that will need to be investigated in the future”, concludes Felipe Cava.

To read the full publication, click here


Top right: Felipe Cava and Sara Hernández, MIMS

Summary figure: by Sara B. Hernández et al.

Emmanuelle Charpentier took the Nobel Prize in Chemistry

Emmanuelle has been awarded jointly with Jennifer Doudna the 2020 Nobel Prize in Chemistry for discovering the groundbreaking CRISPR-Cas9 gene editing technology. She is a former group leader at MIMS, honorary doctor at Umeå University and former visiting professor at UCMR.

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Battling antibiotic resistance

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Research about infectious diseases:

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