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

TitleDual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating .
Publication TypeJournal Article
Year of Publication2019
AuthorsQuezada LLopez, Li K, McDonald SL, Nguyen Q, Perkowski AJ, Pharr CW, Gold B, Roberts J, McAulay K, Saito K, Karakaya SSomersan, Javidnia PElis, de Francisco EPorras, Amieva MMarin, Az SPalomo Dı, Losana AMendoza, Zimmerman M, Liang H-PHo, Zhang J, Dartois V, Sans S, Lagrange S, Goullieux L, Roubert C, Nathan C, Aubé J
JournalACS Infect Dis
Date Published2019 Aug 09

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.

Alternate JournalACS Infect Dis
PubMed ID31184461

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