Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously

Cho, Hongbaek; Wivagg, Carl N.; Kapoor, Mrinal; Barry, Zachary; Rohs, Patricia D. A.; Suh, Hyunsuk; Marto, Jarrod A.; Garner, Ethan C.; Bernhardt, Thomas G.

doi:10.1038/nmicrobiol.2016.172

Cited by 303 publications

(507 citation statements)

References 39 publications

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“…Since MreB has been reported to be associated and to interact with aPBPs456061, it remains plausible that the fraction of MreB exhibiting random diffusion is associated to aPBPs-dependent diffusive PG synthesis. In this scenario, our results would be consistent with the hypothesis put forward by Cho et al 34. that the more broadly conserved PGEM system might build the primary structure of the PG scaffold (and thus be regulated to enable varied growth rates and sizes) while the aPBPs system may fill in gaps that arise during PG expansion and/or damage.…”

Section: Discussionsupporting

confidence: 92%

Contrasting mechanisms of growth in two model rod-shaped bacteria

et al. 2017

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How cells control their shape and size is a long-standing question in cell biology. Many rod-shaped bacteria elongate their sidewalls by the action of cell wall synthesizing machineries that are associated to actin-like MreB cortical patches. However, little is known about how elongation is regulated to enable varied growth rates and sizes. Here we use total internal reflection fluorescence microscopy and single-particle tracking to visualize MreB isoforms, as a proxy for cell wall synthesis, in Bacillus subtilis and Escherichia coli cells growing in different media and during nutrient upshift. We find that these two model organisms appear to use orthogonal strategies to adapt to growth regime variations: B. subtilis regulates MreB patch speed, while E. coli may mainly regulate the production capacity of MreB-associated cell wall machineries. We present numerical models that link MreB-mediated sidewall synthesis and cell elongation, and argue that the distinct regulatory mechanism employed might reflect the different cell wall integrity constraints in Gram-positive and Gram-negative bacteria.

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Section: Discussionsupporting

confidence: 92%

Contrasting mechanisms of growth in two model rod-shaped bacteria

et al. 2017

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“…Mutants of E. coli RodA were introduced using QuikChange mutagenesis into a plasmid containing the allele P lac -pbpA-rodA(WT) (pHC857) 1,2 . Wild-type E.coli cells (strain TB28) were then transformed with the mutant plasmids to generate strains each harboring mutations in the central cavity (E114A, K117A, E114K/K117E, and D159A) and at the RodA-PBP2 interface (L240S, S326A, and L281A).…”

Section: Methodsmentioning

confidence: 99%

“…A second key step is peptide crosslinking, catalyzed by the penicillin binding domains of both aPBPs and bPBPs. Cytological and protein-protein interaction studies indicate that SEDS proteins and bPBPs likely form a complex in cells 1,2 , and evolutionary coupling analysis shows strong co-variation between bPBP and SEDS protein sequences. This is sufficient to map the binding site between bPBPs and RodA to TM8 and TM9 (Figure 4a, b; Extended Data Figure 8), corresponding to the proposed interaction site between the divisome SEDS protein FtsW and its corresponding bPBP, FtsI 10,21,22 .…”

mentioning

confidence: 99%

Structure of the peptidoglycan polymerase RodA resolved by evolutionary coupling analysis

Sjodt

Brock

Dobihal

et al. 2018

Nature

Self Cite

119

139

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The Shape, Elongation, Division, and Sporulation (“SEDS”) proteins are a large family of ubiquitous and essential transmembrane enzymes with critical roles in bacterial cell wall biology. The exact function of SEDS proteins was long enigmatic, but recent work1–3 has revealed that the prototypical SEDS family member RodA is a peptidoglycan polymerase – a role previously attributed exclusively to members of the penicillin binding protein family4. This discovery has made RodA and other SEDS proteins promising targets for the development of next-generation antibiotics. However, little is known regarding the molecular basis for SEDS activity, and no structural data are available for RodA or any homolog thereof. Here, we report the crystal structure of Thermus thermophilus RodA at a resolution of 2.9 Å, determined using evolutionary covariance-based fold prediction to enable molecular replacement. The structure reveals a novel ten-pass transmembrane fold with large extracellular loops, one of which is partially disordered. The protein contains a highly conserved cavity in the transmembrane domain, reminiscent of ligand binding sites in transmembrane receptors. Mutagenesis experiments in Bacillus subtilis and Escherichia coli show that perturbation of this cavity abolishes RodA function both in vitro and in vivo, indicating it is catalytically essential. These results provide a framework for understanding bacterial cell wall synthesis and SEDS protein function.

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“…For instance, penicillin-binding protein disruption by β-lactams stimulates a futile cycle of cell wall synthesis and degradation that depletes cellular resources as part of its toxicity [48,49]. In addition, ATP synthase inhibition by bedaquiline stimulates futile cycling of protons in the respiratory chain [50], which increases oxygen consumption [35] and is lethal to M. tuberculosis [51].…”

Section: Bactericidal Processesmentioning

confidence: 99%

Antibiotic efficacy — context matters

Yang

Bening

Collins

2017

Current Opinion in Microbiology

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Antibiotic lethality is a complex physiological process, sensitive to external cues. Recent advances using systems approaches have revealed how events downstream of primary target inhibition actively participate in antibiotic death processes. In particular, altered metabolism, translational stress and DNA damage each contribute to antibiotic-induced cell death. Moreover, environmental factors such as oxygen availability, extracellular metabolites, population heterogeneity and multidrug contexts alter antibiotic efficacy by impacting bacterial metabolism and stress responses. Here we review recent studies on antibiotic efficacy and highlight insights gained on the involvement of cellular respiration, redox stress and altered metabolism in antibiotic lethality. We discuss the complexity found in natural environments and highlight knowledge gaps in antibiotic lethality that may be addressed using systems approaches.

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Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously

Cited by 303 publications

References 39 publications

Contrasting mechanisms of growth in two model rod-shaped bacteria

Contrasting mechanisms of growth in two model rod-shaped bacteria

Structure of the peptidoglycan polymerase RodA resolved by evolutionary coupling analysis

Antibiotic efficacy — context matters

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