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. 2025 Jun 20;14(7):613.
doi: 10.3390/pathogens14070613.

Antibacterial Evaluation of Tricyclic Antidepressants Against S. aureus and the Possible Pathways of the Mechanism of Action

Vitória Pessoa de Farias Cabral  1   2   3 , Daniel Sampaio Rodrigues  1   2   3 , Lívia Gurgel do Amaral Valente Sá  1   2 , Lara Elloyse Almeida Moreira  1   2 , Cecília Rocha da Silva  1   2 , João Batista de Andrade Neto  1   2   3 , Érica Rayanne Mota da Costa  1   2 , Thais Lima Ferreira  1   2 , Leilson Carvalho de Oliveira  1   2 , Beatriz Oliveira de Souza  1 , Dávylla Rênnia Saldanha Pinheiro  1   2 , Bruno Coêlho Cavalcanti  2 , Islay Lima Magalhães  2 , Manoel Odorico de Moraes  2 , Hélio Vitoriano Nobre Júnior  1   2
Affiliations

Antibacterial Evaluation of Tricyclic Antidepressants Against S. aureus and the Possible Pathways of the Mechanism of Action

Vitória Pessoa de Farias Cabral et al. Pathogens. .

Abstract

The resistance of Staphylococcus aureus to conventional pharmacological treatments has gradually increased. Thus, new therapeutic strategies are needed. Three tricyclic antidepressants (TCAs), amitriptyline (AMT), nortriptyline (NOR), and clomipramine (CLO), stand out with potential in this regard. Thus, the objective of this study was to evaluate the antibacterial activity of TCAs against S. aureus. The methodology used broth microdilution, checkerboard, flow cytometry, fluorescence microscopy, and scanning electron microscopy (SEM) techniques. The results showed that the minimum inhibitory concentration (MIC) of AMT was 256 µg/mL, while the MIC of NOR was 128 µg/mL, and the MIC of CLO was between 64 and 128 µg/mL. The TCAs exhibited bactericidal activity. In the analysis of the association with oxacillin (OXA), AMT exhibited 75% synergism, while NOR and CLO obtained 62.5%. In combination with vancomycin (VAN), AMT and NOR presented 100% additive interactions, while CLO exhibited 62.5% indifferent interactions. The mechanism of TCAs, isolated and combined with OXA, was associated with a reduction in cell viability, resulting from their action on the bacterial genetic material and generation of oxidative stress. Furthermore, the action of the drugs produced intense morphological changes in the bacterial cells. In conclusion, TCAs are a potential alternative for antistaphylococcal therapy.

Keywords: Staphylococcus aureus; amitriptyline; antibacterial; clomipramine; mechanism of action; nortriptyline; synergism; tricyclic antidepressants.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(A) Cell viability of MRSA cells treated with TCAs, assessed by the PI assay. (B) DNA fragmentation of MRSA cells treated with TCAs, evaluated using the TUNEL assay. (C) DNA damage of MRSA cells treated with TCAs, assessed by the comet assay. Significance was defined as * p < 0.05 compared with the respective control and ** p < 0.05 compared with OXA SUB by the Tukey test. The control refers to untreated cells. All tests were performed in at least three replicates.
Figure 2
Figure 2
(A) ROS levels in MRSA cells treated with TCAs, assessed using CM-H2DCFDA. (B) Protein carbonylation in MRSA cells treated with TCAs. Significance was defined as * p  <  0.05 compared with the respective control and ** p  <  0.05 compared with OXA SUB by the Tukey test. The control refers to untreated cells. All tests were performed in at least three replicates.
Figure 3
Figure 3
Morphology of MRSA planktonic cells treated with TCAs isolated and associated with OXA by SEM. (A): Control, B-I: treatments with AMT (B), NOR (C), CLO (D), OXA (E), OXA SUB (F), AMT + OXA (G), NOR + OXA (H), and CLO + OXA (I). Magnification (A): 20,000×, bar: 5 µm; magnification (B–I): 40,000×, bar: 3 µm.
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