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

ABSTRACT: The historical view of ?-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 ?-lactamase inhibitor. However, most antimycobacterial ?-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 ?-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 ?-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A ?-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent ?-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states.

SUBMITTER: Lopez Quezada L 

PROVIDER: S-EPMC7241432 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) in the presence of a β-lactamase inhibitor. However, most antimycobacterial β-lactams kill <i>Mtb</i> 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 <i>Mtb</i> under bot  ...[more]

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