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Atypical Mycobacterium abscessus BlaRI ortholog mediates regulation of energy metabolism but not β-lactam resistance
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  • Lauren E. Bonefont,
  • Haley Davenport,
  • Catherine T. Chaton,
  • Konstantin Korotkov,
  • Kyle Rohde
Lauren E. Bonefont
University of Central Florida Burnett School of Biomedical Sciences
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Haley Davenport
University of Central Florida Burnett School of Biomedical Sciences
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Catherine T. Chaton
University of Kentucky Department of Molecular and Cellular Biochemistry
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Konstantin Korotkov
University of Kentucky Department of Molecular and Cellular Biochemistry
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Kyle Rohde
University of Central Florida Burnett School of Biomedical Sciences

Corresponding Author:kyle.rohde@ucf.edu

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Abstract

Mycobacterium abscessus (Mab) is highly drug resistant, and understanding regulation of antibiotic resistance is critical to future antibiotic development. Regulatory mechanisms controlling Mab’s β-lactamase (Bla Mab) that mediates β-lactam resistance remain unknown. S. aureus encodes a prototypical protease-mediated two-component system BlaRI regulating the β-lactamase BlaZ. BlaR binds extracellular β-lactams, activating an intracellular peptidase domain which cleaves BlaI to derepress blaZ. Mtb encodes homologs of BlaRI, that regulate the Mtb β-lactamase, blaC, but also additional genes related to respiration. We identified orthologs of blaRIMtb in Mab and hypothesized that they regulate blaMab. Surprisingly, neither deletion of blaRIMab nor overexpression of only blaIMab altered blaMab expression or β-lactam susceptibility. However, BlaI Mab did bind to conserved motifs upstream of several Mab genes involved in respiration, yielding a putative regulon that partially overlapped with BlaI Mtb. Prompted by evidence that respiration inhibitors including clofazimine (CFZ) induce the BlaI regulon in Mtb, we found that CFZ triggers induction of blaIRMab and its downstream regulon. Highlighting an important role for BlaRI Mab in adapting to disruptions in energy metabolism, constitutive repression of the BlaI Mab regulon rendered Mab highly susceptible to CFZ. In addition to our unexpected findings that BlaIR Mab does not regulate β-lactam resistance, this study highlights the novel role for mycobacterial BlaRI-type regulators in regulating electron transport and respiration.
Submitted to Molecular Microbiology
Submission Checks Completed
Assigned to Editor
Reviewer(s) Assigned
08 Jul 2024Reviewer(s) Assigned
22 Jul 2024Review(s) Completed, Editorial Evaluation Pending
22 Jul 2024Editorial Decision: Revise Minor
08 Aug 20241st Revision Received
16 Aug 2024Submission Checks Completed
16 Aug 2024Assigned to Editor
19 Aug 2024Reviewer(s) Assigned
26 Aug 2024Review(s) Completed, Editorial Evaluation Pending
26 Aug 2024Editorial Decision: Accept