143026-Advanced resistance studies identify two discrete mechanisms in Staphylococcus aureus to overcome antibacterial compounds that target biotin protein ligase.pdf (2.24 MB)
Advanced resistance studies identify two discrete mechanisms in Staphylococcus aureus to overcome antibacterial compounds that target biotin protein ligase
journal contribution
posted on 2023-05-20, 21:23 authored by 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, Polyak, SWBiotin 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 (<10-9) 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.
History
Publication title
AntibioticsVolume
9Issue
4Article number
165Number
165ISSN
2079-6382Department/School
School of Pharmacy and PharmacologyPublisher
MDPI AGPlace of publication
SwitzerlandRights statement
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/Repository Status
- Open