Harnessing β-Lactam Antibiotics for Illumination of the Activity of Penicillin-Binding Proteins in Bacillus subtilis.

ACS Chemical Biology
Shabnam SharifzadehErin E Carlson

Abstract

Selective chemical probes enable individual investigation of penicillin-binding proteins (PBPs) and provide critical information about their enzymatic activity with spatial and temporal resolution. To identify scaffolds for novel probes to study peptidoglycan biosynthesis in Bacillus subtilis, we evaluated the PBP inhibition profiles of 21 β-lactam antibiotics from different structural subclasses using a fluorescence-based assay. Most compounds readily labeled PBP1, PBP2a, PBP2b, or PBP4. Almost all penicillin scaffolds were coselective for all or combinations of PBP2a, 2b, and 4. Cephalosporins, on the other hand, possessed the lowest IC50 values for PBP1 alone or along with PBP4 (ceftriaxone, cefoxitin) and 2b (cefotaxime) or 2a, 2b, and 4 (cephalothin). Overall, five selective inhibitors for PBP1 (aztreonam, faropenem, piperacillin, cefuroxime, and cefsulodin), one selective inhibitor for PBP5 (6-aminopenicillanic acid), and various coselective inhibitors for other PBPs in B. subtilis were discovered. Surprisingly, carbapenems strongly inhibited PBP3, formerly shown to have low affinity for β-lactams and speculated to be involved in β-lactam resistance in B. subtilis. To investigate the specific roles of PBP3, we developed a...Continue Reading

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Citations

Oct 30, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jonathan HiraChristian S Lentz
Sep 24, 2020·Chembiochem : a European Journal of Chemical Biology·Nathaniel W BrownErin E Carlson
Jan 17, 2021·Antibiotics·Nikola Puvača, Rosa de Llanos Frutos
Jan 21, 2021·ACS Infectious Diseases·Samantha R Levine, Kimberly E Beatty
Dec 30, 2020·Chemical Reviews·Jed F Fisher, Shahriar Mobashery
Sep 28, 2020·Pharmacology & Therapeutics·Anutthaman ParthasarathyKarunakaran Kalesh
Jul 13, 2021·Frontiers in Microbiology·Anne GalinierFrédérique Pompeo
Aug 31, 2021·RSC Chemical Biology·M Rhia L StoneMark A T Blaskovich

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