Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating
| Autor: | Selin Somersan Karakaya, Landys Lopez Quezada, Kohta Saito, Cameron W Pharr, Sara Palomo Dı Az, Kelin Li, Quyen Nguyen, Hsin-Pin Ho Liang, Julia Roberts, Prisca Elis Javidnia, Manuel Marin Amieva, Véronique Dartois, Carl Nathan, Ben Gold, Stéphanie Sans, Matthew D. Zimmerman, Laurent Goullieux, Jeffrey Aubé, Alfonso Mendoza Losana, Esther Porras de Francisco, Christine Roubert, Andrew J. Perkowski, Kathrine McAulay, Stacey L. McDonald, Jun Zhang, Sophie Lagrange |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
DNA Replication Bacilli Tuberculosis medicine.drug_class Pyridines 030106 microbiology Cephalosporin Antitubercular Agents Administration Oral Antimycobacterial Article Microbiology Mycobacterium tuberculosis 03 medical and health sciences Mice Drug Discovery medicine polycyclic compounds Animals Humans biology Chemistry Thiones Callithrix Pyrithione Hep G2 Cells biology.organism_classification medicine.disease bacterial infections and mycoses Cephalosporins High-Throughput Screening Assays 030104 developmental biology Infectious Diseases Female Pharmacophore Mycobacterium |
| Zdroj: | ACS Infect Dis |
| ISSN: | 2373-8227 |
| Popis: | The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a β-lactamase inhibitor. However, most antimycobacterial β-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 β-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3’ that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a β-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A β-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent β-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states. |
| Databáze: | OpenAIRE |
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