<scp><i>yciM</i></scp> is an essential gene required for regulation of lipopolysaccharide synthesis in <i><scp>E</scp>scherichia coli</i>

Mahalakshmi, S.; Sunayana, M. R.; SaiSree, L.; Reddy, Manjula

doi:10.1111/mmi.12452

Cited by 86 publications

(110 citation statements)

References 51 publications

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“…The mechanism of degradation of MepS by the NlpI-Prc system seems to be analogous to that described earlier on the proteolysis of the rate-limiting enzyme of the lipopolysaccharide biosynthesis, LpxC, by an essential membrane-anchored protease FtsH and the TPR-containing adapter protein YciM (19).…”

Section: Discussionsupporting

confidence: 62%

Regulated proteolysis of a cross-link–specific peptidoglycan hydrolase contributes to bacterial morphogenesis

Singh

Parveen

SaiSree

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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126

184

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Bacterial growth and morphogenesis are intimately coupled to expansion of peptidoglycan (PG), an extensively cross-linked macromolecule that forms a protective mesh-like sacculus around the cytoplasmic membrane. Growth of the PG sacculus is a dynamic event requiring the concerted action of hydrolases that cleave the cross-links for insertion of new material and synthases that catalyze cross-link formation; however, the factors that regulate PG expansion during bacterial growth are poorly understood. Here, we show that the PG hydrolase MepS (formerly Spr), which is specific to cleavage of cross-links during PG expansion in Escherichia coli, is modulated by proteolysis. Using combined genetic, molecular, and biochemical approaches, we demonstrate that MepS is rapidly degraded by a proteolytic system comprising an outer membrane lipoprotein of unknown function, NlpI, and a periplasmic protease, Prc (or Tsp). In summary, our results indicate that the NlpI-Prc system contributes to growth and enlargement of the PG sacculus by modulating the cellular levels of the cross-link-cleaving hydrolase MepS. Overall, this study signifies the importance of PG cross-link cleavage and its regulation in bacterial cell wall biogenesis.bacterial morphogenesis | peptidoglycan | regulated proteolysis | MepS | NlpI-Prc P eptidoglycan (PG or murein) is a unique and essential constituent of eubacterial cell walls, thus making it an excellent target for several antimicrobial agents. It is a single, large, extensively cross-linked macromolecule that forms a mesh-like sacculus protecting cells against intracellular turgor pressure in addition to conferring cell shape. Structurally, the PG sacculus is made up of linear glycan strands cross-linked to each other by short peptide chains forming a continuous layer around the cytoplasmic membrane. The glycan strands are made up of alternating N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG) disaccharide units in which NAM is covalently attached to a peptide chain containing 2-to 5-amino acid residues, with the pentapeptide consisting of L-alanine (ala)−D-glutamic acid (glu)−meso-diaminopimelic acid (mDAP)−D-ala−D-ala. Normally, D-ala of one peptide chain is cross-linked to mDAP of another peptide chain of an adjacent glycan strand, resulting in an extensively cross-linked single-or multilayered sacculus (1).Because the murein sacculus totally encircles the cytoplasmic membrane, growth of a cell is tightly coupled to expansion of PG. Growth of the PG sacculus is a dynamic and coordinated event requiring concerted action both of murein hydrolases that facilitate cleavage of cross-links for the insertion of nascent murein material and of synthases that catalyze cross-link formation between adjacent glycan strands (Fig. 1) (2, 3).Escherichia coli encodes multiple PG synthases that catalyze the formation of D-ala−mDAP cross-links in the PG sacculus. The class I enzymes (PBP1a and PBP1b, encoded by mrcA and mrcB, respectively) are bifunctional and possess both glycosyl transferase (GT) and tr...

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Section: Discussionsupporting

confidence: 62%

Regulated proteolysis of a cross-link–specific peptidoglycan hydrolase contributes to bacterial morphogenesis

Singh

Parveen

SaiSree

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

184

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“…Thus, under conditions of direct LPS attack from the environment (i.e., outer membrane), it is highly plausible that this protease functions in parallel with a separate adapter protein that senses the vulnerability of the outer membrane and translates such information to the protease. Indeed, in a similar pattern, FtsH-mediated LpxC degradation has been reported to be dependent on an adapter protein YciM (44). As a result of LpxC being the first committed step in LPS synthesis, it is intuitively reasonable that under conditions that directly alter the membrane structure, cells must attain the desired level of LPS through LpxC regulation irrespective of the concentration of lipid A disaccharide or presence of an active FtsH protein.…”

Section: Discussionmentioning

confidence: 92%

Crosstalk between the lipopolysaccharide and phospholipid pathways during outer membrane biogenesis in Escherichia coli

Emiola

Andrews

Heller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The outer membrane of gram-negative bacteria is composed of phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. LPS is an endotoxin that elicits a strong immune response from humans, and its biosynthesis is in part regulated via degradation of LpxC (EC 3.5.1.108) and WaaA (EC 2.4.99.12/13) enzymes by the protease FtsH . Because the synthetic pathways for both molecules are complex, in addition to being produced in strict ratios, we developed a computational model to interrogate the regulatory mechanisms involved. Our model findings indicate that the catalytic activity of LpxK (EC 2.7.1.130) appears to be dependent on the concentration of unsaturated fatty acids. This is biologically important because it assists in maintaining LPS/phospholipids homeostasis. Further crosstalk between the phospholipid and LPS biosynthetic pathways was revealed by experimental observations that LpxC is additionally regulated by an unidentified protease whose activity is independent of lipid A disaccharide concentration (the feedback source for FtsH-mediated LpxC regulation) but could be induced in vitro by palmitic acid. Further experimental analysis provided evidence on the rationale for WaaA regulation. Overexpression of waaA resulted in increased levels of 3-deoxy-Dmanno-oct-2-ulosonic acid (Kdo) sugar in membrane extracts, whereas Kdo and heptose levels were not elevated in LPS. This implies that uncontrolled production of WaaA does not increase the LPS production rate but rather reglycosylates lipid A precursors. Overall, the findings of this work provide previously unidentified insights into the complex biogenesis of the Escherichia coli outer membrane.lipopolysaccharide | fatty acids | computational model | bacterial membrane regulation

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“…In the heteroresistant strain from patient E, a mutation leading to an amino acid substitution encoded within the yciM gene was found. In Escherichia coli, yciM contributes to cell wall integrity by regulating LPS biosynthesis (46,47), and a deletion in yciM leads to decreased susceptibility to colistin (48). It is possible that the mutation in yciM in K. pneumoniae increases LPS production, leading to higher levels of LPS in the outer membrane, which could titrate out the destabilizing effect of colistin binding to LPS.…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Colistin Heteroresistance in Klebsiella pneumoniae during a Nosocomial Outbreak

Halaby

Küçükköse

Janssen

et al. 2016

Antimicrob Agents Chemother

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dKlebsiella pneumoniae is emerging as an important nosocomial pathogen due to its rapidly increasing multidrug resistance, which has led to a renewed interest in polymyxin antibiotics, such as colistin, as antibiotics of last resort. However, heteroresistance (i.e., the presence of a subpopulation of resistant bacteria in an otherwise susceptible culture) may hamper the effectiveness of colistin treatment in patients. In a previous study, we showed that colistin resistance among extendedspectrum-beta-lactamase (ESBL)-producing K. pneumoniae isolates emerged after the introduction of selective digestive tract decontamination (SDD) in an intensive care unit (ICU). In this study, we investigated heteroresistance to colistin among ESBL-producing K. pneumoniae isolates by using population analysis profiles (PAPs). We used whole-genome sequencing (WGS) to identify the mutations that were associated with the emergence of colistin resistance in these K. pneumoniae isolates. We found five heteroresistant subpopulations, with colistin MICs ranging from 8 to 64 mg/liter, which were derived from five clonally related, colistin-susceptible clinical isolates. WGS revealed the presence of mutations in the lpxM, mgrB, phoQ, and yciM genes in colistin-resistant K. pneumoniae isolates. In two strains, mgrB was inactivated by an IS3-like or ISKpn14 insertion sequence element. Complementation in trans with the wild-type mgrB gene resulted in these strains reverting to colistin susceptibility. The MICs for colistin-susceptible strains increased 2-to 4-fold in the presence of the mutated phoQ, lpxM, and yciM alleles. In conclusion, the present study indicates that heteroresistant K. pneumoniae subpopulations may be selected for upon exposure to colistin. Mutations in mgrB and phoQ have previously been associated with colistin resistance, but we provide experimental evidence for roles of mutations in the yciM and lpxM genes in the emergence of colistin resistance in K. pneumoniae.

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yciM is an essential gene required for regulation of lipopolysaccharide synthesis in Escherichia coli

Cited by 86 publications

References 51 publications

Regulated proteolysis of a cross-link–specific peptidoglycan hydrolase contributes to bacterial morphogenesis

Regulated proteolysis of a cross-link–specific peptidoglycan hydrolase contributes to bacterial morphogenesis

Crosstalk between the lipopolysaccharide and phospholipid pathways during outer membrane biogenesis in Escherichia coli

Genomic Characterization of Colistin Heteroresistance in Klebsiella pneumoniae during a Nosocomial Outbreak

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