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Antimicrobial Properties of Various Psychotropic Drugs Against Broad Range Microorganisms Sadık Kalaycı, Selami Demirci and Fikrettin Şahin* Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Turkey Abstract: Increasing multiple drug resistance of microorganisms to certain antibiotics is a major health problem of the current clinical practice. Therefore, development of novel broad range antimicrobial agents and increasing efficiency of existing antibiotics are under great interest among scientists. Some psychotropic drugs not only reverse microbial antibiotic resistance but also exhibit direct antimicrobial activity against several biological targets. In the present study, 16 different psychotropic drugs including sertraline, paroxetine, aripiprazole, fluvoxamine, moclobemide, venlafaxine, mianserin, trazodone, mirtazapine, clomipramine, alprazolam, escitalopram, citaloprame, fluoxetine, gabapentin and reboxetine have been examined for their antimicrobial properties against wide range of bacteria, yeast and fungi using disc-diffusion and micro-well dilution assays. The results revealed that except FOR gabapentin, venlafaxine, moclobemide and alprazolam, the remaining drugs tested in this study showed various antimicrobial activities. Selective serotonin reuptake inhibitor group drugs including sertraline, paroxetine, fluvoxamine and fluoxetine displayed broad range antibacterial activity compared to other psychotropic drugs. Among them, sertraline was also found to be effective against Candida albicans and Aspergillus niger. Exploring antimicrobial activities will increase the use and application of these psychotropic drugs in clinical approaches. However, in vivo studies and clinical trials are strictly required to evaluate efficiencies of these chemicals for the treatment of systemic microbial infections.
Keywords; Antipsychotics, antidepressant, antibacterial, antimicrobial, sertraline, SSRI. INTRODUCTION There are some synthetic or natural medicinal compounds, referred as non-antibiotics, which are effective against microbial metabolism. A number of non-antibiotic drugs including non-steroidal anti-inflammatory drugs, calcium channel blockers and antidepressants have been reported to display biocidal or biostatic activity on microbial community after chlorpromazine, a dopamine antagonist, was found to have antimicrobial properties in 1959 [1]. These non-antibiotic drugs act in different manners on microbial growth. They may have direct antimicrobial activity (antimicrobial non-antibiotics), increase the *Address correspondence to this author at the Genetics and Bioengineering Department, Faculty of Engineering and Architecture, Yeditepe University Kayisdagi, Istanbul, Turkey; Tel: +90 (216) 578 0619; Fax: +90 (216) 578 0829; E-mail:
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efficiency of an antibiotic as given together (helper compounds), or change the pathogenicity of microorganisms or activity on the physiology such as modulating macrophage activity [2]. Multiple drug resistance among highly infective microorganisms generates a major obstacle to clinical applications in recent years. As development of a new broad range antimicrobial agent is difficult and takes several years, increasing the activity of existing antibiotics would be a future solution to this challenge. Nonantibiotics including antidepressants have been shown to decrease minimum inhibition concentration (MIC) levels of several antibiotics mainly by inhibiting efflux pump activity [3-6]. Beyond acting synergistically, some psychotic drugs per se exhibit antimicrobial characteristics. They have been effective against both gram negative and positive bacteria [1, 7, 8], yeast [9], fungi [10], and protozoa [11]. Although it is known that psychotic drugs mainly inhibit efflux © 2014 Bentham Science Publishers
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Table 1.
Kalaycı et al.
The list of microorganisms used in the study. Pseudomonas aeruginosa Escherichia coli Klebsiella pneumoniae Gram Negative Proteus vulgaris Yersinia enterocolitica Acinetobacter baumannii Staphylococcus aureus
Bacteria
Bacillus subtilis Staphylococcus epidermidis Gram Positive Methicillin-resistant Staphylococcus aureus (MRSA) Vancomycin-resistant Enterococci (VRE) Enterococcus faecalis Acid-fast
Mycobacterium tuberculosis
Yeast
Candida albicans
Fungi
Aspergillus niger
pump action, exact mechanism of growth inhibition is not clearly elucidated yet. Besides, antimicrobial activities of several psychotic drugs have not been investigated and comparison of activities between these drugs is not clearly defined in the literature to expand their use in clinical approaches. In the current study, 16 psychotic drugs belonging to different groups including selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitor (SNRI), noradrenergic and specific serotonergic antidepressants (NaSSA), tricyclic antidepressant, atypical antidepressant, serotonin antagonist and reuptake inhibitor (SARI), benzodiazepine, reversible monoamine oxidase inhibitor (MAOI), GABA analog and norepinephrine reuptake inhibitor were investigated for their antimicrobial activities against broad range of microorganisms including bacteria, yeast and fungi. MATERIALS AND METHODS Microbial Strains and Media The compounds were individually tested against a total 15 microorganisms belonging to 13 bacteria, a yeast and a fungus species in the
present study (Table 1). They were provided by the Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Turkey. Microbial identifications were confirmed using Microbial Identification and Biolog Systems. Tryptic soy agar (TSA), sabouraud dextrose agar (SDA), potato dextrose agar (PDA), tryptic soy broth (TSB), sabouraud dextrose broth (SDB) were obtained from Merck (Darmstadt, Germany). Middlebrook 7H10 agar with OADC enrichment and Middlebrook 7H9 broth with OADC enrichment were purchased from BD Diagnostic Systems. Unless otherwise noted, all other reagents were the highest grade available and obtained from Sigma-Aldrich (Taufkirchen, Germany). Psychotropic Drugs The list of psychotropic drugs used in the study and their respective groups are given in Table 2. Sertraline HCl (Sanovel, Istanbul, 306.22 g/mol), paroxetine HCl (Novartis, Istanbul, 329.3 g/mol), aripiprazole (Bristol Myers squibb, Istanbul, 448.38 g/mol), fluvoxamine maleate (Abbott labs, Istanbul, 318.33 g/mol), moclobemide HCl (Roche, Istanbul, 268.74 g/mol), venlafaxine HCl (Wyeth, Istanbul, 277.40 g/mol), mianserin HCl
Antimicrobial Properties of Various Psychotropic Drugs
(Santa farma, Istanbul, 264.36 g/mol), trazodone HCl (Santa farma, Istanbul, 371.86 g/mol), mirtazapine (Organon İlaç, Istanbul, 265.35 g/mol), clomipramine HCl (Novartis pharma, Istanbul, 314.90 g/mol), alprazolam (Pfizer, Istanbul, 308.76 g/mol), escitalopram oxalate (Abdi Ibrahim ilaç, Istanbul, 296.34 g/mol), reboxetine (Pfizer, Istanbul, 313.39 g/mol) and citaloprame HBr (Abdi Ibrahim ilaç, Istanbul, 324.39 g/mol) were dissolved in dimethyl sulfoxide (Me2SO), and fluoxetine HCl (Biofarma, Istanbul, 309.33 g/mol) and gabapentin (Pfizer, Istanbul, 171.23 g/mol) were dissolved in distilled water at a stock concentration of 4096mg/L. Disc-Diffusion Assay Antimicrobial tests were carried out using disc diffusion assay as described previously [12]. 100µl of microbial suspension containing 108 CFU/mL of bacteria, 108 CFU/mL of M. tuberculosis, 106 CFU/mL of yeast and 104 spore/mL of fungi spread on TSA, Middlebrook 7H10 agar was supplemented with oleic acid-albumin-dextrosecatalase (OADC) enrichment, SDA and PDA, respectively. Blank discs (6mm in diameter) impregnated with 17µl of dissolved drugs (70µg/disc) were placed on the inoculated agar plates. Me2SO and distilled water employed to dissolve synthetic drugs were used as negative controls. Ofloxacin (5µg/disc), levofloxacin (10µg/disc) and nystatin (100u/disc) were used as positive controls to determine the sensitivity of strains/isolates tested for bacteria, M. tuberculosis and fungi, respectively. The inoculated plates were incubated 24 h for bacterial strains and 48 h for yeast at 36 ± 1ºC, and 72 h for fungi isolates at 27 ± 1ºC. M. tuberculosis inoculated plates were incubated at 37 °C and 5% CO2 in an incubator for 3 weeks. Antimicrobial activity was determined by measuring the zone of inhibition around the discs. Micro-Well Dilution Assay The MIC values were determined for the microbial strains, which were found to be sensitive to compounds in disc-diffusion assay as described previously [13]. Briefly, suspensions containing microbial inoculum prepared from fresh broth cultures were adjusted to 0.5 McFarland standard turbidity. Compounds dissolved in Me2SO and dH2O were first diluted to the highest concentration 1024mg/L to be tested, and then
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serial two-fold dilutions were made to obtain a concentration range from 2 to 1024µg/mL in sterile test tubes containing TSB for bacteria, Middlebrook 7H9 broth medium with OADC enrichment and 0.05% Tween80 for M. tuberculosis, SDB for yeast and fungi. 95µL of the respective broth and 5µL of the inoculum were dispensed into each well of 96-well plates. 100µL serially diluted solutions of compounds were added into consecutive wells on each strip. The last wells of each line containing 195µL of the broth without compound and 5µL of the inoculum were used as negative controls. 200µL of fresh broth was used as positive control. Contents of each well were mixed on plate shaker at 300 rpm for 20 s and then incubated 24 h for bacterial strains and 48 h for yeast at 36 ± 1ºC, and 72 h for fungi isolates at 27 ± 1ºC. M. tuberculosis inoculated plates were incubated at 36 ± 1ºC and 5% CO2 for 3 weeks. Microbial growth in each medium was determined by reading absorbance at 600 nm for bacteria, 530 nm for fungal isolates using the ELx 800 universal microplate reader (Biotek Instrument inc, Highland Park, Vermont, USA). The MIC was defined as the lowest concentration of the compounds that inhibit the microbial growth. Minimum Bactericidal (MBC) and Fungicidal (MFC) Concentration Minimum bactericidal/fungicidal (MBC/MFC) values were determined as the lowest concentration in which no bacterial/fungal growth was detected. 5µl samples from MIC level and upper concentration wells of micro-well dilution assay were put on TSA, Middlebrook 7H10 with OACD, SDA, and PDA for bacteria, M. tuberculosis, yeast and fungi, respectively. Inoculated plates were incubated 24 h for bacterial strains (3 weeks for M. tuberculosis) and 48 h for yeast at 36 ± 1ºC, and 72 h for fungi isolates at 27 ± 1ºC. The lowest concentrations of drugs which show no bacterial or fungal growth were recorded as MBC or MFC values. RESULTS AND DISCUSSION Increasing multiple drug resistance of microorganisms to certain antibiotics is a major health problem of the current clinical practice. Resistant bacteria including methicillin resistant Staphylococcus spp. and Enterococcus spp. are
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Table 2. The list of psychotics drugs used in the study. Sertraline Paroxetine Fluoxetine Selective serotonin reuptake inhibitor (SSRI) Fluvoxamine Citaloprame Escitalopram Serotonin-norepinephrine reuptake inhibitor (SNRI)
Venlafaxine Mianserin
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine Tricyclic antidepressant (TCA)
Clomipramine
Dopamine agonist
Aripiprazole
Serotonin antagonist and reuptake inhibitor (SARI)
Trazodone
Benzodiazepine
Alprazolam
Reversible monoamine oxidase inhibitor (MAOI)
Moclobemide
GABA analog-Antiepileptic
Gabapentin
Norepinephrine reuptake inhibitor
Reboxetine
responsible for almost one-third of all communityacquired infections [14]. Therefore, scientists have been trying to find new broad range antimicrobial agents along with potentiators/sensitizers for existing antimicrobials. In this study, 16 different psychotropic drugs have been examined for their antimicrobial properties against bacteria, yeast and fungi. Antimicrobial characteristics of these drugs were determined by disc-diffusion and micro-well dilution assay, and evaluated by the presence of inhibition zones, zone diameters, MIC and MBC/MFC values. Zone of diameters obtained from disc-diffusion assay are shown in Table 3. The results showed that some chemicals exhibited a broad range of antimicrobial activity while some of them remained ineffective against any microbial species tested. Gabapentin, venlafaxine, moclobemide and alprazolam were found to be completely ineffective against all microorganisms tested. On the other hand, other drugs exerted various antimicrobial characteristics. In particular, sertraline, a SSRI group antidepressant, displayed the strongest and widest range of antimicrobial activities against all bacteria, yeast and fungi, except P. aeruginosa. According to the discdiffusion assay results, not only sertraline but also other examined drugs were interestingly found to
be inactive against P. aeruginosa. One scenario to this situation might be that P. aeruginosa has protective outer membrane efflux pumps which prevent bacteria from high concentrations of antimicrobial agents accumulation inside the cytoplasm or low outer membrane permeability controlled by the OprD porin production [15, 16]. Apart from sertraline, paroxetine and fluoxetine, other SSRI members, were found to exert remarkable antibacterial activity, especially against gram positive bacteria. B. subtilis and S. epidermidis were more sensitive species to the psychotropic drugs than other gram positive and negative bacteria. On the other hand, none of the drugs were found to effective against C. albicans, except sertraline and reboxentine. Lass-Flörl and his colleagues [17] have reported that 7-29mg/L sertraline concentration was enough to inhibit the growth of C. albicans whereas our findings showed that 128mg/L of sertraline was required (Table 4). This may be explained by the differences in drug tolerance of yeast isolate used in these studies. All chemicals were also tested for their antifungal activities against A. niger. Sertraline, aripiprazole and reboxetine were noted to display inhibitory effect on fungal growth. According to the MIC and MBC/MFC results,
Antimicrobial Properties of Various Psychotropic Drugs
Table 3.
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199
Antimicrobial activities of psychotropic drugs on different microorganisms determined based on discdiffusion assay.
Psychotropic Drugs*/ Sert# Parox Fluox Fluvox Citalo Escit Venla Mian Mirta Clomip Aripip Trazo Alpra Moclo Gaba Rebox PC NC Microorganisms P. aeruginosa
-a
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
20
-
E. coli
15b
14
9
9
8
-
-
8
-
-
-
-
-
-
-
-
28
-
K. pneumoniae
11
16
18
10
9
9
-
8
-
-
7
-
-
-
-
-
28
-
S. aureus
15
10
10
-
8
-
-
8
-
12
-
-
-
-
-
-
24
-
Y. enterocolitica
12
14
16
10
-
8
-
-
-
11
-
8
-
-
-
-
22
-
B. subtilis
21
14
25
11
9
9
-
10
-
22
7
-
-
-
-
-
26
-
P. vulgaris
14
15
15
10
-
8
-
10
7
11
-
8
-
-
-
-
18
-
A. baumannii
15
15
18
12
12
9
-
10
7
12
-
8
-
-
-
-
14
-
S. epidermidis
24
15
19
7
-
-
-
16
-
13
-
-
-
-
-
-
22
-
MRSA
14
9
10
-
-
-
-
8
-
10
-
-
-
-
-
-
22
-
VRE
15
14
8
-
-
-
-
7
-
10
-
-
-
-
-
-
20
-
M. tuberculosis
16
14
10
-
-
-
-
-
-
10
-
-
-
-
-
-
20
-
E. faecalis
12
15
10
-
-
-
-
-
-
8
-
-
-
-
-
-
16
-
C. albicans
7
-
-
-
-
-
-
-
-
-
-
-
-
-
-
14
18
-
A. niger
9
-
-
-
-
-
-
-
-
-
7
-
-
-
-
7
20
-
*Tested concentration of psychotropic drugs in disc-diffusion assay is 4096µg/ml. # Sert: Sertraline, Parox: paroxetine, Fluox: fluoxetine, Fluvox: fluvoxamine, Aripip: aripiprazole, Moclo: moclobemide, Venla: venlafaxine, Mian: mianserin, Trazo: trazodone, Mirta: mirtazapine, Clomip: clomipramine, Escit: escitalopram, Citalo: citaloprame, Gaba: gabapentin, Rebox: reboxentine, Alpra: alprazolam, PC: Ofloxacin (5 µg/disc), Levofloxacin (10µg/disc) and nystatin (100 u/disc) were used for bacteria, M. tuberculosis and fungi, respectively. NC: Distilled water. a No activity was observed, b All values were expressed in mm.
sertraline exhibited superior antifungal effect among other drugs (Table 4). As in convenient with these findings, sertraline, fluoxetine, citaloprame and reboxetine have been tested against Aspergillus spp. in an in vitro study, and sertraline has been reported to be the most effective drug [10]. Interestingly, SSRI group drugs (sertraline, paroxetine, and fluoxetine) and clomipramine exhibited better antibacterial activity against vancomycin resistant enterococci (VRE) compared to parental E. feacalis strain. In contrast to this observation MRSA was more resistant to chemicals tested with respect to parental S. aureus. As results of positive control (ofloxacin) for VRE, E. feacalis, MRSA and S. aureus in disc-diffusion assay were similar, it may be speculated that VRE tested in the study is sensitive to antimicrobial agents other than vancomycin. Further studies with
a great number of resistant and sensitive strains are required to investigate the exact mode of action. M. tuberculosis especially multiple drug resistant strains, causing an estimated 2 million death annually, is one of the major challenges in current medicine [18]. Although there have been encouraging studies for the treatment of tuberculosis [19, 21], drug development pipeline for tuberculosis does not offer an adequate number of alternative treatment options. Herein, we demonstrated that M. tuberculosis were the most sensitive microorganisms tested against psychotropic drugs including sertraline, paroxetine, fluoxetine and clomipramine. The drugs were found to display inhibitory effect at as low concentration as 2mg/L which is close to maximum psychotropic drug serum levels in human metabolism. Therefore, in vivo studies should be conducted to examine potential
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Kalaycı et al.
Table 4. MIC and MBC/MFC values of psychotropic drugs determined by micro-well dilution assay.
Microbial Species
SERT#
PAROX
FLUOX
FLUVOX
CITALO
MIC MBC/MFC MIC MBC/MFC MIC MBC/MFC MIC MBC/MFC MIC
ESCIT
MBC/MFC
MIC
MBC/MFC
E. coli
4*
8
128
128
16
32
32
128
256
256
-
-
K. pneumonia
16
16
64
128
32
32
32
256
512
1024
256
˃1024
S. aureus
4
8
128
128
4
64
-a
-
256
1024
-
-
B. subtilis
8
8
256
256
4
64
64
256
256
256
256
512
P. vulgaris
16
16
32
64
32
64
64
128
-
-
128
128
A. baumannii
4
4
64
64
32
32
128
128
256
256
128
512
Y. entercolitica
16
16
64
64
64
64
256
256
512
1024
S. epidermidis
4
8
32
32
32
32
64
256
-
-
-
-
MRSA
32
32
128
128
128
128
-
-
-
-
-
-
M. tuberculosis
2
4
8
8
8
16
VRE
8
8
32
64
16
32
-
-
-
-
-
-
E. faecalis
16
16
64
64
32
64
-
-
-
-
-
-
C. albicans
128
128
-
-
-
-
-
-
-
-
-
-
A. niger
64
64
-
-
-
-
-
-
-
-
-
-
E. coli
256
256
-
-
-
-
-
-
-
-
-
-
K. pneumonia
256
256
-
-
-
-
256
512
-
-
-
-
S. aureus
128
256
-
-
32
32
-
-
-
-
-
-
B. subtilis
128
256
-
-
32
32
512
˃1024
-
-
-
-
P. vulgaris
128
128
256
256
32
32
-
-
128
512
-
-
A. baumannii
128
128
128
256
16
64
-
-
512
1024
-
-
Y. entercolitica
-
-
-
-
64
64
-
-
512
512
-
-
S. epidermidis
64
64
-
-
8
8
-
-
-
-
-
-
MRSA
256
1024
-
-
32
128
-
-
M. tuberculosis
-
-
16
16
-
-
-
-
VRE
256
256
-
-
64
64
-
-
-
-
-
-
E. faecalis
512
512
-
-
128
128
-
-
-
-
-
-
C. albicans
-
-
-
-
-
-
-
-
-
-
128
512
A. niger
-
-
-
-
-
-
128
128
-
-
256
512
#
Sert: Sertraline, Parox: paroxetine, Fluox: fluoxetine, Fluvox: fluvoxamine, Aripip: aripiprazole, Mian: mianserin, Trazo: trazodone, Mirta: mirtazapine, Clomip: clomipramine, Escit: escitalopram, Citalo: citaloprame, Rebox: reboxentine. *All values were expressed in mg/L. a Not determined.
antimycobacterial activities of these chemicals alone or in combination with approved tuberculosis drugs.
The main limiting factor of non-antibiotic drugs to display their antimicrobial characteristics in mammalian system is that the maximum serum
Antimicrobial Properties of Various Psychotropic Drugs
Current Psychopharmacology, 2014, Volume 3, No. 3
level remains (approx. 1mg/L) lower than the concentration required to inhibit microbial growth [1]. However, these levels might be sufficient to modify microbial metabolism and act synergistically with certain antibiotics [22, 23]. In addition, it has been claimed that 0.75mg/L sertraline, lower than the tissue concentration in vivo, resulted in lack of hyphal transformation and decrease in virulence for Candida spp. [9]. Apart from modifying microbial metabolism, they can also increase the efficiency of certain antibiotics at low concentrations as they are administered together [1]. These studies suggest that even low tissue concentration of psychotropic drugs alone or in combination with other antimicrobials may be effective against various type of microorganisms. CONCLUSION
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In conclusion, the results revealed that some psychotropic drugs, mainly SSRI groups, exhibited appreciable antibacterial, and moderate or low anticandidal and antifungal activities. Apart from known antimicrobial non-antibiotics in the literature, this is the first study, to our best knowledge, to show antibacterial, anticandidal and antifungal properties of several psychotropic drugs including escitalopram, mirtazapine and trazodone. Given the challenges of de novo antimicrobial drug development, exploring antimicrobial properties of these safe and pharmaceutically known drugs will increase their use in clinics. However, further studies are highly warranted to investigate the non-antibiotics’ mode of action on microbial growth to design effective formulations that will be effective at low concentrations. An additional consideration is that animal models and clinical trials are required to expand the use of psychotropic drugs or their combination with antibiotics for the treatment of microbial infections.
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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS This work was supported University (Istanbul, Turkey).
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Received: November 11, 2014
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Revised: April 14, 2015
Accepted: April 17, 2015
