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Identification of a new family of peptidoglycan transpeptidases reveals unusualcrosslinking is essential for viability inC. difficile

ABSTRACT: Identification of a new family of peptidoglycan transpeptidases reveals unusualcrosslinking is essential for viability inC. difficile

PROVIDER: PRJNA1125117 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29444116_1.fastq.gz	Fastqsanger.gz
	SRR29444116_2.fastq.gz	Fastqsanger.gz
	SRR29444117_1.fastq.gz	Fastqsanger.gz
	SRR29444117_2.fastq.gz	Fastqsanger.gz
	SRR29444118_1.fastq.gz	Fastqsanger.gz

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Identification of a new family of peptidoglycan transpeptidases reveals unusualcrosslinking is essential for viability inC. difficile

Project description:Most bacteria are surrounded by a peptidoglycan cell wall composed of glycan strands held together by short peptide crosslinks. There are two major types of crosslinks, termed 4-3 and 3-3 based on the amino acids involved. 4-3 crosslinks are created by penicillin-binding proteins (PBPs), while 3-3 crosslinks created byL,D-transpeptidases (LDTs). In well studied bacteria 3-3 crosslinks comprise only about 10% of the total and are not essential. However, in the opportunistic intestinal pathogenClostridioides difficile,about 70% of the crosslinks are 3-3. We show here that 3-3 crosslinks and LDTs are essential for viability inC. difficile. We also show thatC. difficilehas five LDTs, three with a YkuD catalytic domain as in all previously known LDTs and two with a VanW catalytic domain, whose function was until now unknown. The five LDTs exhibit extensive functional redundancy. VanW domain proteins are found in many Gram-positive bacteria but scarce in other lineages. We tested seven non-C. difficileVanW domain proteins and confirmed LDT activity in three cases. In summary, our findings uncover a new family of peptidoglycan crosslinking enzymes, assign a catalytic function to VanW domains, and demonstrate that 3-3 crosslinking is essential for viability inC. difficile, the first time this has been shown in any bacterial species.

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Identification of a new family of peptidoglycan transpeptidases reveals atypical crosslinking is essential for viability in <i>Clostridioides difficile</i>.

Project description:Clostridioides difficile, the leading cause of antibiotic-associated diarrhea, relies primarily on 3-3 crosslinks created by L,D-transpeptidases (LDTs) to fortify its peptidoglycan (PG) cell wall. This is unusual, as in most bacteria the vast majority of PG crosslinks are 4-3 crosslinks, which are created by penicillin-binding proteins (PBPs). Here we report the unprecedented observation that 3-3 crosslinking is essential for viability in C. difficile. We also report the discovery of a new family of LDTs that use a VanW domain to catalyze 3-3 crosslinking rather than a YkuD domain as in all previously known LDTs. Bioinformatic analyses indicate VanW domain LDTs are less common than YkuD domain LDTs and are largely restricted to Gram-positive bacteria. Our findings suggest that LDTs might be exploited as targets for antibiotics that kill C. difficile without disrupting the intestinal microbiota that is important for keeping C. difficile in check.

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The Serine/Threonine kinase PrkC of Clostridioides difficile regulates export of CD1135, a septal peptidoglycan hydrolase

Project description:Cell growth and division require a balance between synthesis and hydrolysis of the peptidoglycan (PG). Inhibition of PG synthesis or uncontrolled PG hydrolysis can be lethal for the cells, making it imperative to control peptidoglycan hydrolase (PGH) activity. The activity of several enzymes involved in PG synthesis is regulated by serine/threonine kinase (STKs). In firmicutes, inactivation of genes encoding STKs is associated with a range of phenotypes including cell division defects and changes in cell wall metabolism, but only a few kinase substrates have been identified. We previously demonstrated that the STK PrkC plays an important role in cell division, cell wall metabolism and drug resistance in Clostridioides difficile. In this work, we identified and characterized a PGH, CD1135 that is a PrkC substrate. We showed that CD1135 hydrolyses PG between daughter cells to allow cell separation. We demonstrated that CD1135 phosphorylation inhibits CD1135 its export, therefore controlling the hydrolytic activity in the cell wall. High level of CD1135 in the cell wall leads to cell elongation, whereas low level causes cell separation defects. We provided evidences that the STK signaling pathway regulates PGHs homeostasis to control PG hydrolysis during growth and cell division.

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Identification of a family of peptidoglycan transpeptidases reveals that <i>Clostridioides difficile</i> requires noncanonical cross-links for viability.

Project description:Most bacteria are surrounded by a cell wall that contains peptidoglycan (PG), a large polymer composed of glycan strands held together by short peptide cross-links. There are two major types of cross-links, termed 4-3 and 3-3 based on the amino acids involved. 4-3 cross-links are created by penicillin-binding proteins, while 3-3 cross-links are created by L,D-transpeptidases (LDTs). In most bacteria, the predominant mode of cross-linking is 4-3, and these cross-links are essential for viability, while 3-3 cross-links comprise only a minor fraction and are not essential. However, in the opportunistic intestinal pathogen Clostridioides difficile, about 70% of the cross-links are 3-3. We show here that 3-3 cross-links and LDTs are essential for viability in C. difficile. We also show that C. difficile has five LDTs, three with a YkuD catalytic domain as in all previously known LDTs and two with a VanW catalytic domain, whose function was until now unknown. The five LDTs exhibit extensive functional redundancy. VanW domain proteins are found in many gram-positive bacteria but scarce in other lineages. We tested seven non-C. difficile VanW domain proteins and confirmed LDT activity in three cases. In summary, our findings uncover a previously unrecognized family of PG cross-linking enzymes, assign a catalytic function to VanW domains, and demonstrate that 3-3 cross-linking is essential for viability in C. difficile, the first time this has been shown in any bacterial species. The essentiality of LDTs in C. difficile makes them potential targets for antibiotics that kill C. difficile selectively.

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