Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross‐Linking Activity of a Transpeptidase of l,d Specificity

• Published in: Chemistry : a European journal Vol. 27; no. 10; pp. 3542 - 3551
• Main Authors: Saidjalolov, Saidbakhrom, Edoo, Zainab, Fonvielle, Matthieu, Mayer, Louis, Iannazzo, Laura, Arthur, Michel, Etheve‐Quelquejeu, Mélanie, Braud, Emmanuelle
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 15.02.2021; Wiley Subscription Services, Inc
• Subjects: Anti-Bacterial Agents - pharmacology; Antibiotics; carbapenem; Carbapenems; Carbapenems - chemistry; Cell Wall; Cell walls; Chemistry; Chemistry, Multidisciplinary; esterification; Gram-negative bacteria; Hydroxyl groups; Inactivation; Meropenem; Optimization; Peptidoglycan; Peptidoglycans; Peptidomimetics; Peptidyl Transferases; Pharmacokinetics; Physical Sciences; Science & Technology; Substrates; transpeptidase; Tuberculosis; peptidoglycan; peptidomimetics; carbapenem; transpeptidase; esterification
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202004831

The carbapenem class of β‐lactams has been optimized against Gram‐negative bacteria producing extended‐spectrum β‐lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d‐transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β‐lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido‐carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems. Main and side chains mimetics: A synthetic route to carbapenems modified at position C8 was developed to assess the impact of mimetics of the main and side chains of peptidoglycan precursors on cross‐linking activity of l,d‐transpeptidase from E. faecium. Substitution at position C8 can be therefore used to modulate the properties of carbapenem without deleterious effects on the efficacy of l,d‐transpeptidase inhibition.