N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis
| Autor: | Robert Schnell, Paola Dal Monte, Michael Landreh, Eva Maria Steiner, Martina Cirillo, Carolina Caso, Daria Giacomini, Tomas Bohn Pessatti, Giulia Martelli, Francesco Bisognin |
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| Přispěvatelé: | Martelli, Giulia, Pessatti, Tomas Bohn, Steiner, Eva Maria, Cirillo, Martina, Caso, Carolina, Bisognin, Francesco, Landreh, Michael, Monte, Paola Dal, Giacomini, Daria, Schnell, Robert |
| Rok vydání: | 2020 |
| Předmět: |
Carbapenem
Tuberculosis antibiotic resistance medicine.drug_class β-lactam Clinical Biochemistry LdtMt2 Drug resistance Mycobacterium tuberculosi Microbial Sensitivity Tests Antimycobacterial beta-Lactams 01 natural sciences Biochemistry Meropenem Microbiology Mycobacterium tuberculosis chemistry.chemical_compound Drug Discovery Drug Resistance Bacterial medicine Molecular Biology Pharmacology biology Molecular Structure 010405 organic chemistry L D-transpeptidase biology.organism_classification medicine.disease 0104 chemical sciences Anti-Bacterial Agents chemistry adduct structure Peptidyl Transferases Lactam Molecular Medicine covalent inhibitor Target protein medicine.drug |
| Zdroj: | Cell chemical biology. 28(9) |
| ISSN: | 2451-9448 |
| Popis: | Summary Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated in vitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds. |
| Databáze: | OpenAIRE |
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