Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating .

The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against () in the presence of a β-lactamase inhibitor. However, most antimycobacterial β-lactams kill 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 under both replicating and nonreplicating conditions, neither activity requiring a β-lactamase inhibitor. Studies showed that activity against nonreplicating required the release of the pyrithione, independent of the known class A β-lactamase, BlaC. In contrast, replicating 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.