Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating Mycobacterium tuberculosis. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • June 11, 2019

Research

keywords

  • Antitubercular Agents
  • Cephalosporins
  • DNA Replication
  • Mycobacterium tuberculosis
  • Pyridines
  • Thiones

Identity

PubMed Central ID

  • PMC7241432

Scopus Document Identifier

  • 85070903143

Digital Object Identifier (DOI)

  • 10.1021/acsinfecdis.9b00112

PubMed ID

  • 31184461

Additional Document Info

volume

  • 5

issue

  • 8