Tricyclic amine antidepressants suppress β‐lactam resistance in methicillin‐resistant Staphylococcus aureus (MRSA) by repressing mRNA levels of key resistance genes
Abstract
Methicillin‐resistant Staphylococcus aureus (MRSA) is the leading cause of recurrent infections in humans including endocarditis, pneumonia, and toxic shock syndrome. Novel therapeutics to treat MRSA and other resistant bacteria are urgently needed. Adjuvant therapy, which uses a non‐toxic compound to repotentiate the toxic effects of an existing antibiotic, is an attractive response to the growing resistance crisis. Herein, we describe the evaluation of structurally related, FDA‐approved tricyclic amine antidepressants that selectively repotentiate MRSA to β‐lactam antibiotics. Our results identify important structural features of the tricyclic amine class for β‐lactam adjuvant activity. Furthermore, we describe the mechanism of action for our lead compound, amoxapine, and illustrate that it represses the mRNA levels of key β‐lactam resistance genes in response to β‐lactam treatment. This work is novel in that it highlights an important class of small molecules with the ability to simultaneously inhibit production of both β‐lactamase and penicillin binding protein 2a.
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TCAs act by repressing the expression of β-lactam resistance genes, while thioridazine acts by inhibiting the expression of genes involved in cell wall biosynthesis.
“It has been reported that do so, TCAs act by repressing the expression of β-lactam resistance genes, while thioridazine acts by inhibiting the expression of genes involved in cell wall biosynthesis [98,99].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [98]
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Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications
Caldara, M., & Marmiroli, N. (2021) · Pharmaceuticals · doi:10.3390/ph14090915 · Cited by 54 · see citing works
- Authors
- Gillard, K., Miller, H. B., & Blackledge, M. S.
- Affiliations
- High Point University (US)
- Corresponding author
- Miller, Heather B.
- Blackledge, Meghan S.
- Venue
- Chemical Biology & Drug Design
- Publisher
- Wiley
- Published
- 2018-07-18
- Volume
- 92
- Issue
- 5
- Pages
- 1822-1829
- ISSN
- 1747-0277 (ISSN-L)
- 1747-0285
- OpenAlex
- W2810143726
- Cited by
- 20
- References
- 17
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 7 · 2021: 1 · 2020: 2 · 2019: 3
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Biology & Drug Design (publishedVersion)
- PubMed (publishedVersion)
- Funders
- High Point University (High Point, NC)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- methicillin-resistant Staphylococcus aureus, beta-lactam resistance, adjuvant therapy, amoxapine, beta-lactamase inhibition, penicillin-binding protein 2a, mRNA repression, antibiotic resistance genes
- MeSH terms
- Anti-Bacterial Agents, Antidepressive Agents, Tricyclic, Bacterial Proteins, beta-Lactamases, Microbial Sensitivity Tests, Oxacillin, RNA, Messenger, Drug Resistance, Bacterial, Methicillin-Resistant Staphylococcus aureus
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