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Open AccessArticle

Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

1
School of Biological Sciences, University of Adelaide, South Australia 5005, Australia
2
School of Physical Sciences, University of Adelaide, South Australia 5005, Australia
3
Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, SA 5005, Australia
4
Institute of Photonics and Advanced Sensing (IPAS), School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Present address: School of Biomedical Sciences, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and The Royal Melbourne Hospital, Melbourne, Victoria 3000, Australia.
§
Present address: Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA 6009, Australia.
Present address: Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
Present address: Albert Einstein College of Medicine, New York City, NY 10461, USA.
**
Present address: School of Pharmacy and Pharmacology, The University of Tasmania, Hobart, Tasmania 7005, Australia.
††
Present address: South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
‡‡
Present address: College of Science and Engineering, Flinders University, Bedford Park, SA 5042, Australia.
§§
Present address: Health and Biomedical Innovation, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
Antibiotics 2020, 9(4), 165; https://doi.org/10.3390/antibiotics9040165
Received: 23 March 2020 / Revised: 3 April 2020 / Accepted: 4 April 2020 / Published: 6 April 2020
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 (<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. View Full-Text
Keywords: antimicrobial resistance; Gram-positive bacteria; Staphylococcus aureus; advanced resistance studies; biotin; biotin protein ligase; BirA; novel antibacterials antimicrobial resistance; Gram-positive bacteria; Staphylococcus aureus; advanced resistance studies; biotin; biotin protein ligase; BirA; novel antibacterials
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Hayes, A.J.; Satiaputra, J.; Sternicki, L.M.; Paparella, A.S.; Feng, Z.; Lee, K.J.; Blanco-Rodriguez, B.; Tieu, W.; Eijkelkamp, B.A.; Shearwin, K.E.; Pukala, T.L.; Abell, A.D.; Booker, G.W.; Polyak, S.W. Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase. Antibiotics 2020, 9, 165.

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