Dual Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating Mycobacterium tuberculosis Articles uri icon

publication date

  • June 2019

start page

  • 1433

end page

  • 1445


  • 8


  • 5

International Standard Serial Number (ISSN)

  • 2373-8227


  • 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 pyrithionecontaining
    cephalosporins arises from two mechanisms that kill
    mycobacteria in different metabolic states.


  • mycobacterium; tuberculosis; cephalosporin; pyrithione; β-lactamase; antimycobacterial