Remodeling of Crossbridges Controls Peptidoglycan Cross-linking Levels in Bacterial Cell Walls

Pidgeon, Sean E.; Apostolos, Alexis J.; Pires, Marcos M.

doi:10.1101/840405

Cited by 1 publication

(2 citation statements)

References 45 publications

(36 reference statements)

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“…[28][29][30][31][32][33] Yet, single D-amino acid PG probes cannot interrogate how the stem peptide structure (or its many chemical modifications) can control PG crosslinking or processing. We 34,35 , and others [36][37][38][39] , have recently demonstrated that fluorescently tagged structural mimics of nascent TP substrates can be crosslinked into the growing PG scaffold of live cells, thus hijacking the cell wall machinery (Scheme 2B). Indeed, we have shown that penta-, tetra-, and tri-peptides that are analogs of the PG stem peptide are accepted by TPs to varying extents.…”

Section: Introductionmentioning

confidence: 99%

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Facile Synthesis and Metabolic Incorporation of m-DAP Bioisosteres Into Cell Walls of Live Bacteria

et al. 2020

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Bacterial cell walls contain peptidoglycan (PG), a scaffold that provides proper rigidity to resist lysis from internal osmotic pressure and a barrier to protect cells against external stressors. It consists of repeating sugar units with a linkage to a stem peptide that becomes highly crosslinked by cell wall transpeptidases (TP). While synthetic PG fragments containing L-Lysine in the 3 rd position on the stem peptide are easier to access, those with meso-diaminopimelic acid (m-DAP) pose a severe synthetic challenge. Herein, we describe a solid phase synthetic scheme based on widely available building blocks to assemble meso-cystine (m-CYT), which mimics key structural features of m-DAP. To demonstrate proper mimicry of m-DAP, cell wall probes were synthesized with m-CYT in place of m-DAP and evaluated for their metabolic processing in live bacterial cells. We found that m-CYT-based cell wall probes were properly processed by TPs in various bacterial species that endogenously contain m-DAP in their PG. Additionally, we have used hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) and Molecular Dynamics (MD) simulations to explore the influence of m-DAP analogs on the PG crosslinking. The results showed that crosslinking mechanism of transpeptidases occurred through a concerted process. We anticipate that this strategy, which is based on the use of inexpensive and commercially available building blocks, can be widely adopted to provide greater accessibility of PG mimics for m-DAP containing organisms.

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Section: Introductionmentioning

confidence: 99%

“…Indeed, we have shown that penta-, tetra-, and tri-peptides that are analogs of the PG stem peptide are accepted by TPs to varying extents. 34,35 However, to this point we had been unable to investigate the role of m-DAP (and its modifications) because of the challenge in building m-DAP containing peptides.…”

Section: Introductionmentioning

confidence: 99%