Induction of AmpC-Mediated β-Lactam Resistance Requires a Single Lytic Transglycosylase in Agrobacterium tumefaciens

Figueroa-Cuilan, Wanda M.; Howell, Matthew; Richards, Christopher M.; Randich, Amelia M.; Yadav, Akhilesh Kumar; Cava, Felipe; Brown, Pamela

doi:10.1128/aem.00333-22

Cited by 7 publications

(20 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A. tumefaciens encodes a canonical inducible AmpC β-lactamase system where the import of anhydromuropeptides controls β-lactamase expression through the regulator AmpR (21, 22)(Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

“…The presence of an AmpC induction system based on released muropeptides has been previously reported in A. tumefaciens (21), but the mechanism through which muropeptides enter the cell has not been revealed until now. As a soil bacterium, A. tumefaciens likely encounters β-lactam antibiotics in the environment, so the presence of an inducible β-lactamase system could be a way to counter these.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

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

Gilmore

Cava

2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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

Gilmore

Cava

2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The presence of an AmpC induction system based on released muropeptides has been previously reported in A. tumefaciens 25 , but the mechanism through which muropeptides enter the cell has not been revealed until now. As a soil bacterium, A. tumefaciens likely encounters β-lactam antibiotics in the environment produced by competing organisms to interact or fight for their niche 42 , so the presence of an inducible β-lactamase system could be a way to counter these.…”

Section: Discussionmentioning

confidence: 98%

“…A. tumefaciens encodes a canonical inducible AmpC β-lactamase system where the import of anhydromuropeptides controls β-lactamase expression through the regulator AmpR 25,26 (Fig. 3A).…”

Section: Role Of Pg Recycling In β-Lactam Resistance In a Tumefaciensmentioning

confidence: 99%

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

Gilmore

Cava

2022

Nat Commun

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Novel regulation and details of the mechanisms involved probably could be unraveled if any transcription factors or specific motifs in DNA level were to be predicted and proven. 5,6 If there are any predicted TFs, which is unique in ESBL-producing E. coli, then we recommend that this issue be unraveled in future studies.…”

mentioning

confidence: 99%

A Response to Research Article “Cefmetazole Resistance Mechanism for Escherichia Coli Including ESBL-Producing Strains” [Letter]

Panjaitan¹,

Lestari²

2022

IDR

View full text Add to dashboard Cite

The work performed by Ito et al was much appreciated since the authors addressed a novel and important issue in antibiotic rational uses, particularly the resistance of Cefmetazole in ESBL-producing E. coli and the involved gene regulations. Cefmetazole have been used as an alternative to carbapenems in addition to the use of quinolone and trimethoprim or sulfamethoxazole in infection cases caused by ESBL-producing E. coli. 1,2 In their study, 14 ESBLproducing and 12 ESBL-non-producing E. coli from 63 E. coli strains in total were isolated clinically. 3 The ESBLproducing ability of those E. coli isolates did not determine their behavior against Cefmetazole treatment in this study, since the MIC of either ESBL-non producing or ESBL-producing E. coli isolates vary (still relatively low at 1-4 μg/mL) in the first culture. Eleven strains of total 25 isolate gained resistance after being cultured with Cefmetazole at a low dose. Interestingly, after passage culture with the antibacterial-free medium, only 4 strains from these 11 isolates remain resistant to Cefmetazole, while the others gained susceptibility. The purpose of the authors was to unravel the mechanisms involved in the resistance acquisition against Cefmetazole in ESBL-producing E. coli clinical isolates, with the use of ESBL-non-producing isolates as the controls.The previous study, reported more than thirty years ago, addressed the potential mechanism of action of Cefmetazole in methicillin and cephem-resistant (MR) strains of Staphylococcus aureus. 4 However, the progression in this particular issue is relatively slower than the mechanism study of other type of antibiotic, especially in ESBL-producing E. coli. In this study, authors tried to explore the mechanism of how Cefmetazole resistance acquisition occurred in ESBLproducing E. coli isolates. Therefore, the transcription (mRNA) levels of porin encoding genes (ompF, ompC, phoE), chromosomal β-lactamase AmpC encoding genes (acrA, yhiV, mdfA), and drug efflux pump were detected in this particular study. However, as also discussed well in their discussion section, these mechanisms were not the novel part.Moreover, the authors also combined the use of Relebactam (the β-lactamase inhibitor) in observing the effects obtained in Cefmetazole use in E. coli isolates, which resulted in alteration in Cefmetazole susceptilbity. The addition of Relebactam suppressed the resistance toward Cefmetazole. However, the remaining question is, while β-lactamase was inhibited, what mechanism was underlying the suppression of Cefmetazole resistance acquisition? Is the effect caused by inhibiting β-lactamase alone enough to suppress antibiotic resistance? Should the upstream regulators be checked for details of their mechanisms, since the authors themselves mentioned that the Relebactam probably caused the porin deficiency. Novel regulation and details of the mechanisms involved probably could be unraveled if any transcription factors or specific motifs in DNA level were to be predicted and proven. 5,6 If there are any pred...

show abstract

Induction of AmpC-Mediated β-Lactam Resistance Requires a Single Lytic Transglycosylase in Agrobacterium tumefaciens

Cited by 7 publications

References 89 publications

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

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

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

A Response to Research Article “Cefmetazole Resistance Mechanism for Escherichia Coli Including ESBL-Producing Strains” [Letter]

Contact Info

Product

Resources

About