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

• DOI: 10.1021/acschembio.0c00618
• Publication Date: 2020-10-20T15:22:46Z
• Authors: Alexis J. Apostolos; Julia M. Nelson; José Rogério A. S...; Jerônimo Lameira; Alecia M. Achimovich; Andreas Gahlmann; Cláudio N. Alves; Marcos M. Pires
• Keywords: 0301 basic medicine; 03 medical and health sciences; Bacteria; Cell Wall; Mycobacterium smegmatis; Cystine; Peptidoglycan; Diaminopimelic Acid

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