Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases

Rácz, Bálint; Spengler, Gabriella

doi:10.3390/antibiotics12010137

Cited by 19 publications

(20 citation statements)

References 132 publications

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“…52 Furthermore, various techniques can be utilized to inhibit efflux pumps, including reducing efflux gene expression by controlling genetic regulation, restructuring previously used antibiotics, blocking the formation of functional efflux pumps, preventing substrate binding at the efflux pump's active site, and disrupting the energy mechanism responsible for activating the pumps. 53,54 The current research presents fresh insights into mechanisms Omid Azizi https://orcid.org/0000-0001-7759-8029…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, the analogs of Mastoparan‐L exhibited significantly reduced toxicity and demonstrated the ability to enhance the effectiveness of rifampicin and gentamicin antibiotics in managing bacterial sepsis in mouse models 52 . Furthermore, various techniques can be utilized to inhibit efflux pumps, including reducing efflux gene expression by controlling genetic regulation, restructuring previously used antibiotics, blocking the formation of functional efflux pumps, preventing substrate binding at the efflux pump's active site, and disrupting the energy mechanism responsible for activating the pumps 53,54 …”

Section: Discussionmentioning

confidence: 99%

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Amphiphilic peptide Mastoparan‐B induces conformational changes within the AdeB efflux pump, down‐regulates adeB gene expression, and restores antibiotic susceptibility in an MDR strain of Acinetobacter baumannii

et al. 2023

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Mastoparan B (MP‐B) is an amphiphilic peptide with a potent antimicrobial activity against most Gram‐negative bacteria. However, there is little information available on the inhibition of the Acinetobacter baumannii resistance‐nodulation‐cell‐division (RND) efflux pump using this antimicrobial peptide. Here, we carried out a series of in‐silico experiments to find the mechanisms underlying the anti‐efflux activity of MP‐B using a multi‐drug resistant (MDR) strain of A. baumannii (AB). According to our findings, MP‐B demonstrated a potent antibacterial activity against an MDR‐AB (minimum inhibitory concentration [MIC] = 1 μg/mL) followed by a 20‐fold reduction in the adeB gene expression in the presence of sub‐MIC of this peptide. Using Groningen Machine for Chemicals Simulation (GROMACS) via PyMOL Graphical User Interface (GUI), (we observed that, the AdeB transporter had conserved helix‐turn‐helix regions and a tight pore rich in Phe and Ala residues. To understand how inhibition of the AdeB is achieved, we generated 20 apo‐MP‐B poses using the InterPep and SiteMap tools. The high‐quality model was created by homology modeling and used for docking via AutoDock/Vina to identify the MP‐B binding sites. We established that the most apo‐MP‐B formed H‐bonds to the backbone of five amino acids in the Helix‐5. As a result, the dihedral angles of the involved amino acids shift by 9.0–9.6 Ǻ, causing a change in the conformation of the AdeB protein. This led to helix conformation stereoisomerization and block the AdeB activity. MP‐B presumably has dual mechanisms. (1) It blocks the AdeB transporter by changing its conformation. (2) MP‐B influences the adeB gene expression by binding to G‐protein which laterally controls efflux regulators like MarA, RamA, SoxS, and Rob proteins.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Amphiphilic peptide Mastoparan‐B induces conformational changes within the AdeB efflux pump, down‐regulates adeB gene expression, and restores antibiotic susceptibility in an MDR strain of Acinetobacter baumannii

et al. 2023

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“…First-and second-generation antipsychotic drugs possess antibacterial properties, suggesting that the elimination of translocated microbes may drive symptomatic relief in psychosis [224]. This is further substantiated by the current efforts to repurpose several antipsychotic drugs as antibiotics [225].…”

Section: Antipsychotics As Antibacterialsmentioning

confidence: 97%

Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

Sfera

2023

Reports

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In 1957, Arvid Carlsson discovered that dopamine, at the time believed to be nothing more than a norepinephrine precursor, was a brain neurotransmitter in and of itself. By 1963, postsynaptic dopamine blockade had become the cornerstone of psychiatric treatment as it appeared to have deciphered the “chlorpromazine enigma”, a 1950s term, denoting the action mechanism of antipsychotic drugs. The same year, Carlsson and Lindqvist launched the dopamine hypothesis of schizophrenia, ushering in the era of psychopharmacology. At present, six decades later, although watered down by three consecutive revisions, the dopamine model remains in vogue. The latest emendation of this paradigm proposes that “environmental and genetic factors” converge on the dopaminergic pathways, upregulating postsynaptic transmission. Aryl hydrocarbon receptors, expressed by the gut and blood–brain barrier, respond to a variety of endogenous and exogenous ligands, including dopamine, probably participating in interoceptive awareness, a feed-back loop, conveying intestinal barrier status to the insular cortex. The conceptualization of aryl hydrocarbon receptor as a bridge, connecting vagal terminals with the microbiome, may elucidate the aspects of schizophrenia seemingly incongruous with the dopamine hypothesis, such as increased prevalence in urban areas, distance from the equator, autoantibodies, or comorbidity with inflammatory bowel disease and human immunodeficiency 1 virus. In this review article, after a short discussion of schizophrenia outcome studies and insight, we take a closer look at the action mechanism of antipsychotic drugs, attempting to answer the question: do these agents exert their beneficial effects via both dopaminergic and nondopaminergic mechanisms? Finally, we discuss potential new therapies, including transcutaneous vagal stimulation, aryl hydrocarbon receptor ligands, and restoring the homeostasis of the gut barrier.

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“…Thioridazine is a first-generation phenothiazine antipsychotic drug that has gained attention in recent years as a repurposed drug for the treatment of cancer [ 15 , 16 ], as well as bacterial [ 17 , 18 ] and mycobacterial infections [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Besides its intrinsic antimicrobial activity, thioridazine inhibits efflux pumps that mediate drug resistance in a number of microbes. For this reason, thioridazine has been tested in combination with other drugs in order to either potentiate drug effect or to revert drug resistance [ 16 , 21 ]. As examples, thioridazine acts in synergy with the beta-lactam antibiotic, dicloxacillin, to kill methicillin-resistant Staphylococcus aureus in vitro and in a mouse model of peritonitis [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Antileishmanial Activity of Thioridazine

Sifontes-Rodríguez,

Mollineda-Diogo,

Monzote-Fidalgo

et al. 2023

Acta Parasit.

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Introduction Leishmaniasis is a neglected disease with high prevalence and incidence in tropical and subtropical areas. Existing drugs are limited due to cost, toxicity, declining efficacy and unavailability in endemic places. Drug repurposing has established as an efficient way for the discovery of drugs for a variety of diseases. Purpose The objective of the present work was testing the antileishmanial activity of thioridazine, an antipsychotic agent with demonstrated effect against other intracellular pathogens. Methods The cytotoxicity for mouse peritoneal macrophages as well as the activity against Leishmania amazonensis, Leishmania mexicana and Leishmania major promastigotes and intracellular amastigotes, as well as in a mouse model of cutaneous leishmaniasis, were assessed. Results Thioridazine inhibited the in vitro proliferation of promastigotes (50% inhibitory concentration—IC50—values in the range of 0.73 µM to 3.8 µM against L. amazonensis, L. mexicana and L. major) and intracellular amastigotes (IC50 values of 1.27 µM to 4.4 µM for the same species). In contrast, in mouse peritoneal macrophages, the 50% cytotoxic concentration was 24.0 ± 1.89 µM. Thioridazine inhibited the growth of cutaneous lesions and reduced the number of parasites in the infected tissue of mice. The dose of thioridazine that inhibited lesion development by 50% compared to controls was 23.3 ± 3.1 mg/kg and in terms of parasite load, it was 11.1 ± 0.97 mg/kg. Conclusions Thioridazine was effective against the promastigote and intracellular amastigote stages of three Leishmania species and in a mouse model of cutaneous leishmaniasis, supporting the potential repurposing of this drug as an antileishmanial agent.

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Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases

Cited by 19 publications

References 132 publications

Amphiphilic peptide Mastoparan‐B induces conformational changes within the AdeB efflux pump, down‐regulates adeB gene expression, and restores antibiotic susceptibility in an MDR strain of Acinetobacter baumannii

Amphiphilic peptide Mastoparan‐B induces conformational changes within the AdeB efflux pump, down‐regulates adeB gene expression, and restores antibiotic susceptibility in an MDR strain of Acinetobacter baumannii

Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

In Vitro and In Vivo Antileishmanial Activity of Thioridazine

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