A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis.
Regulation of cell wall assembly is essential for bacterial survival and contributes to pathogenesis and antibiotic tolerance in Mycobacterium tuberculosis (Mtb). However, little is known about how the cell wall is regulated in stress. We found that CwlM, a protein homologous to peptidoglycan amidases, coordinates peptidoglycan synthesis with nutrient availability. Surprisingly, CwlM is sequestered from peptidoglycan (PG) by localization in the cytoplasm, and its enzymatic function is not essential. Rather, CwlM is phosphorylated and associates with MurA, the first enzyme in PG precursor synthesis. Phosphorylated CwlM activates MurA ~30 fold. CwlM is dephosphorylated in starvation, resulting in lower MurA activity, decreased cell wall metabolism, and increased tolerance to multiple antibiotics. A phylogenetic analysis of cwlM implies that localization in the cytoplasm drove the evolution of this factor. We describe a system that controls cell wall metabolism in response to starvation, and show that this regulation contributes to antibiotic tolerance.
Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States.
Cara C
0000-0001-7645-6221
CC
Boutte
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States.
Christina E
CE
Baer
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States.
Kadamba
K
Papavinasasundaram
Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States.
Weiru
W
Liu
Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States.
Michael R
MR
Chase
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States.
Xavier
X
Meniche
Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States.
Sarah M
SM
Fortune
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States.
Christopher M
CM
Sassetti
Department of Computer Science, Texas A and M University, Texas, United States.
Thomas R
TR
Ioerger
Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
Eric J
0000-0001-5120-962X
EJ
Rubin
D002473:Cell Wall / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000235:genetics / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational
D010457:Peptidoglycan; D009238:N-Acetylmuramoyl-L-alanine Amidase
Mycobacterium smegmatis; Mycobacterium tuberculosis; antibiotics; biochemistry; infectious disease; microbiology; peptidoglycan; regulation