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Advanced resistance studies identify two discrete mechanisms in Staphylococcus aureus to overcome antibacterial compounds that target biotin protein ligase

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Hayes, AJ, Satiaputra, J, Sternicki, LM, Paparella, AS, Feng, ZK, Lee, KJ, Blanco-Rodriguez, B, Tieu, W, Eijkelkamp, BA, Shearwin, KE, Pukala, TL, Abell, AD, Booker, GW and Polyak, SW 2020 , 'Advanced resistance studies identify two discrete mechanisms in Staphylococcus aureus to overcome antibacterial compounds that target biotin protein ligase' , Antibiotics, vol. 9, no. 4 , doi: 10.3390/antibiotics9040165.

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Abstract

Biotin protein ligase (BPL) inhibitors are a novel class of antibacterial that target clinically important methicillin-resistant Staphylococcus aureus (S. aureus). In S. aureus, BPL is a bifunctional protein responsible for enzymatic biotinylation of two biotin-dependent enzymes, as well as serving as a transcriptional repressor that controls biotin synthesis and import. In this report, we investigate the mechanisms of action and resistance for a potent anti-BPL, an antibacterial compound, biotinyl-acylsulfamide adenosine (BASA). We show that BASA acts by both inhibiting the enzymatic activity of BPL in vitro, as well as functioning as a transcription co-repressor. A low spontaneous resistance rate was measured for the compound (-9) and whole-genome sequencing of strains evolved during serial passaging in the presence of BASA identified two discrete resistance mechanisms. In the first, deletion of the biotin-dependent enzyme pyruvate carboxylase is proposed to prioritize the utilization of bioavailable biotin for the essential enzyme acetyl-CoA carboxylase. In the second, a D200E missense mutation in BPL reduced DNA binding in vitro and transcriptional repression in vivo. We propose that this second resistance mechanism promotes bioavailability of biotin by derepressing its synthesis and import, such that free biotin may outcompete the inhibitor for binding BPL. This study provides new insights into the molecular mechanisms governing antibacterial activity and resistance of BPL inhibitors in S. aureus.

Item Type: Article
Authors/Creators:Hayes, AJ and Satiaputra, J and Sternicki, LM and Paparella, AS and Feng, ZK and Lee, KJ and Blanco-Rodriguez, B and Tieu, W and Eijkelkamp, BA and Shearwin, KE and Pukala, TL and Abell, AD and Booker, GW and Polyak, SW
Keywords: antimicrobial resistance, Gram-positive bacteria, Staphylococcus aureus, advanced resistance studies, biotin, biotin protein ligase, BirA, novel antibacterials
Journal or Publication Title: Antibiotics
Publisher: MDPI AG
ISSN: 2079-6382
DOI / ID Number: 10.3390/antibiotics9040165
Copyright Information:

Copyright 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/

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