A new class of cell wall-recycling L,D-carboxypeptidase determines β-lactam susceptibility and morphogenesis in <i>Acinetobacter baumannii</i>

Dai, Yunfei; Pinedo, Víctor; Tang, Amy Y.; Cava, Felipe; Geisinger, Edward

doi:10.1101/2021.09.22.461454

Cited by 3 publications

(3 citation statements)

References 82 publications

(129 reference statements)

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“…Many bacteria outside the typical models lack orthologs of key PG recycling enzymes, but have others 4 , suggesting there are alternative enzymes or pathways to be discovered. For example, it was recently uncovered that both Vibrio cholerae 16 and Acinetobacter baumanii 38,39 have different functional analogs of the E. coli LD-carboxypeptidase LdcA with a separate but convergent evolution. We noticed that many bacteria belonging to the Rhizobiales and Rhodobacterales orders of the Alphaproteobacteria lacked an AmpG transporter despite having orthologs of the other key PG recycling enzymes AmpD and NagZ.…”

Section: Discussionmentioning

confidence: 99%

Peptidoglycan recycling mediated by an ABC transporter in the plant pathogen Agrobacterium tumefaciens

Gilmore

Cava

2022

Nat Commun

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During growth and division, the bacterial cell wall peptidoglycan (PG) is remodelled, resulting in the liberation of PG muropeptides which are typically reinternalized and recycled. Bacteria belonging to the Rhizobiales and Rhodobacterales orders of the Alphaproteobacteria lack the muropeptide transporter AmpG, despite having other key PG recycling enzymes. Here, we show that an alternative transporter, YejBEF-YepA, takes over this role in the Rhizobiales phytopathogen Agrobacterium tumefaciens. Muropeptide import by YejBEF-YepA governs expression of the β-lactamase AmpC in A. tumefaciens, contributing to β-lactam resistance. However, we show that the absence of YejBEF-YepA causes severe cell wall defects that go far beyond lowered AmpC activity. Thus, contrary to previously established Gram-negative models, PG recycling is vital for cell wall integrity in A. tumefaciens. YepA is widespread in the Rhizobiales and Rhodobacterales, suggesting that YejBEF-YepA-mediated PG recycling could represent an important but overlooked aspect of cell wall biology in these bacteria.

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Section: Discussionmentioning

confidence: 99%

Peptidoglycan recycling mediated by an ABC transporter in the plant pathogen Agrobacterium tumefaciens

Gilmore

Cava

2022

Nat Commun

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“…Many bacteria outside the typical models lack orthologs of key PG recycling enzymes, but have others (4), suggesting there are alternative enzymes or pathways to be discovered. For example, it was recently uncovered that both Vibrio cholerae (14) and Acinetobacter baumanii (30, 31) have different functional analogs of the E. coli LD-carboxypeptidase LdcA with a separate but convergent evolution. We noticed that many bacteria belonging to the Rhizobiales and Rhodobacterales orders of the Alphaproteobacteria lacked an AmpG transporter despite having orthologs of the other key PG recycling enzymes AmpD and NagZ.…”

Section: Discussionmentioning

confidence: 99%

Peptidoglycan recycling mediated by an ABC transporter in the plant pathogenAgrobacterium tumefaciens

Gilmore

Cava

2022

Preprint

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During growth and division, the bacterial cell wall peptidoglycan (PG) is remodelled, a process which results in the liberation of soluble PG fragments called muropeptides. These fragments can be released to the environment, where they can have far-reaching consequences in signalling and interspecies interactions, or reinternalized and recycled by the cell. Bacteria belonging to the Rhizobiales and Rhodobacterales groups of the Alphaproteobacteria lack the canonical muropeptide transporter AmpG, despite encoding orthologs of the other key PG recycling enzymes AmpD and NagZ in their genomes. Using high-throughput transposon sequencing (Tn-Seq), we identified an alternative ATP-binding-casette (ABC) family transporter, YejBEF-YepA, which takes over this role in the Rhizobiales phytopathogen Agrobacterium tumefaciens. The broad-spectrum peptide transporter "core" YejBEF functions with a PG-specific periplasmic substrate-binding protein (SBP) YepA to transport muropeptides into the cytoplasm for recycling. Muropeptide import by YejBEF-YepA governs the expression of the β-lactamase AmpC in A. tumefaciens through an AmpR repression system, and its absence confers hypersensitivity to β-lactam antibiotics. However, we show that the absence of YejBEF-YepA causes severe cell wall defects that go beyond the lowered AmpC activity. Thus, contrary to previously established Gram-negative models, PG recycling is vital for cell wall integrity in A. tumefaciens. YepA is widespread in the Alphaproteobacteria including in many clinically and environmentally relevant bacteria, suggesting that YejBEF-YepA-mediated PG recycling could represent an important but overlooked aspect of cell wall biology in the Alphaproteobacteria.

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“…While processing pentapeptides to tetrapeptides is important for peptidoglycan maturation, it is not clear why PBP5 overexpression resolves division defects in PBP3-depleted organisms (1, 36, 37), but these studies suggest PBP5 could function similarly in A. baumannii . A recent report speculated that following PBP5-dependent tetrapeptide formation, an unidentified periplasmic LD-carboxypeptidase could modify periplasmic tetrapeptides to tripeptides (51), which were proposed to be the primary substrate of PBP3 (1, 52); however, increased PBP3 activity is dependent on lipid II availability, which presumably shifts peptidoglycan biogenesis towards division, away from elongation. If this pathway were intact in A. baumannii , it would be possible that PBP5-dependent increases in tripeptide pools could increase substrate availability to PBP3 despite depletion, which could potentially rescue the division defect.…”

Section: Discussionmentioning

confidence: 99%

PBP1A directly interacts with the divisome complex to promote septal peptidoglycan synthesis in Acinetobacter baumannii

Kang

Boll

2022

Preprint

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The class A penicillin-binding proteins (aPBPs), PBP1A and PBP1B, are major peptidoglycan synthases that synthesize more than half of the peptidoglycan per generation in Escherichia coli. Whereas aPBPs have distinct roles in peptidoglycan biosynthesis during growth (i.e., elongation and division), they are semi-redundant; disruption of either is rescued by the other to maintain envelope homeostasis and promote proper growth. Acinetobacter baumannii is a nosocomial pathogen that demonstrated a high propensity to overcome antimicrobial treatment. A. baumannii encodes both PBP1A and PBP1B (encoded by mrcA and mrcB, respectively), but only mrcA deletion decreased fitness and contributed to colistin resistance through inactivation of lipooligosaccharide biosynthesis, indicating that PBP1B was not functionally redundant with PBP1A activity. While previous studies suggested a distinct role for PBP1A in division, it was unknown if its role in septal peptidoglycan biosynthesis was direct. Here, we show that A. baumannii PBP1A has a direct role in division through interactions with divisome components. PBP1A localizes to septal sites during growth, where it interacts with the transpeptidase, PBP3, an essential division component that regulates daughter cell formation. PBP3 overexpression was sufficient to rescue the division defect in ΔmrcAA. baumannii; however, PBP1A overexpression was not sufficient to rescue the septal defect when PBP3 was inhibited, suggesting their activity is not redundant. Overexpression of a major DD-carboxypeptidase, PBP5, also restored the canonical A. baumannii coccobacilli morphology in ΔmrcA cells. Together, these data support a direct role for PBP1A in A. baumannii division and highlights its role as a septal peptidoglycan synthase.

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A new class of cell wall-recycling L,D-carboxypeptidase determines β-lactam susceptibility and morphogenesis in Acinetobacter baumannii

Cited by 3 publications

References 82 publications

Peptidoglycan recycling mediated by an ABC transporter in the plant pathogen Agrobacterium tumefaciens

Peptidoglycan recycling mediated by an ABC transporter in the plant pathogen Agrobacterium tumefaciens

Peptidoglycan recycling mediated by an ABC transporter in the plant pathogenAgrobacterium tumefaciens

PBP1A directly interacts with the divisome complex to promote septal peptidoglycan synthesis in Acinetobacter baumannii

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