Antibacterial properties of thioridazine
The emergence and spread of antibiotic-resistant strains of microorganisms reduces the effectiveness of antibiotic therapy and requires finding solutions to problems, one of which is the study of antimicrobial properties in drugs of various pharmacological groups.
The purpose of the work was to summarize the data on the antibacterial activity of thioridazine and its derivatives to determine the feasibility and prospects of creating new antibacterial drugs on their basis.
The paper presents literature data on the effects of thioridazine on the causative agent of tuberculosis, antistaphylococcal activity, susceptibility of plasmodium and trypanosoma.
The antibacterial activity of the drug was established within in vitro studies with the determination of MIC towards gram-positive and gram-negative microorganisms, ex vivo using macrophage lines, as well as within in vivo experiments on mice.
It is established that the neuroleptic thioridazine is characterized by pronounced anti-tuberculosis activity, the mechanism of action is associated with the impact on the cell membrane of M. tuberculosis, inactivation by calmodulin and inhibition of specific NADH-dehydrogenase type II.
The literature data indicate that thioridazine is able to increase the activity of isoniazid against the strains of mycobacteria that are susceptible and resistant to its action. It has been established that resistance to thioridazine in antibiotic-resistant M. tuberculosis strains is not formed.
The drug is characterized by its ability to inhibit the growth and reproduction of both methicylin-sensitive (MSSA) and methicilin-resistant (MRSA) strains of Staphylococcus aureus, which has been proven within in vitro experiments.
The effectiveness of thioridazine has been proven within in vivo experiments in case of skin infection and sepsis caused by S. aureus. Antimicrobial effect of the drug is also observed towards to plasmodium (P. falciparum) and trypanosomes (Trypanosoma spp.).
Currently, the synthesis of thioridazine derivatives is carried out to identify compounds with a pronounced antibacterial effect. Some of the first synthesized compounds are not inferior or superior to thioridazine by the inhibitory effect.
Thus, these data suggest that drugs of different pharmacological groups, including drugs that affect the nervous system - thioridazine and its derivatives, can be a source of replenishment of the arsenal of antimicrobial drugs to control such threatening infections as tuberculosis and diseases caused by polyresistant strains of microorganisms.
2. Gelband H., Miller-Petrie M., Pant S. et al. The state of the world’s antibiotics 2015. – Washington: Center for Disease Dynamics, Economics & Policy, 2015. – 79 с.
3. European Antimicrobial Resistance Surveillance Network (EARS-Net) [Електронний ресурс] // European Centre for Disease Prevention and Control. – 2014. – Режим доступу: http://ecdc.europa.eu/en/publications/Publications/ antimicrobial-resistance-europe-2014.pdf
4. Antibiotic resistance threats in the United States, 2013 [Електронний ресурс]. – 2013. – Режим доступу: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf
5. Kalayci S. Non-antibiotics: psychotropic drugs // EC Microbiology. – 2017. – V. 10.1. P. 1921.
6. Vandevelde N. M., Tulkens P. M., Van Bambeke F. Modulating antibiotic activity towards respiratory bacterial pathogens by co-medications: a multi-target approach // Drug Discov. Today. – 2016. – V. 21, N 7. – P. 1114–1129. http://doi.org/10.1016/j.drudis.2016.04.001
7. Prasad V., Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval // JAMA Intern Med. 2017. V. 177, N 11. Р. 1569–1575. http://doi.org/10.1001/jamainternmed.2017.3601
8. Andersson J. A., Fitts E. C., Kirtley M. L. et al. New role for FDA-approved drugs in combating antibiotic-resistant bacteria // Antimicrob Agents Chemother. 2016. V. 60, N 6. Р. 37173729. http://doi.org/10.1128/AAC.00326-16.
9. Obad J., Šuškovic J., Kos B. Antimicrobial activity of ibuprofen: new perspectives on an «Old» non-antibiotic drug // Eur. J. Pharmac. Sci. 2015. V. 71. P. 93–98. http://doi.org/10.1016/j.ejps.2015.02.011
10. Varga B., Csonka А., Csonka А. Possible biological and clinical applications of phenothiazines // Anticancer res. 2017. V. 37, N 11. P. 59835993. http://doi.org/10.21873/anticanres.12045
11. Dastidar S. G., Kristiansen J. E., Molnar J., Amaral L. Role of phenothiazines and structurally similar compounds of plant origin in the fight against infections by drug resistant bacteria // Antibiotics. – 2013. – V. 2, N 1. – P. 58–72. http://doi.org/10.3390/antibiotics2010058
12. Aybey A., Usta A., Demirkan E. Effects of psychotropic drugs as bacterial efflux pump inhibitors on quorum sensing regulated behaviors // J. Microbiol. Biotech. Food Sci. – 2014. – V. 4, N 2. – P. 128–131. http://doi.org/10.15414/jmbfs.2014.4.2.128-131
13. Kalayci S., Sahin F., Selami D. Antimicrobial properties of various psychotropic drugs against broad range microorganisms // Current Psychopharmacology. – 2014. – V. 3. – P. 195–202. http://doi.org/10.2174/2211556004666150520230121
14. Thanacoody H. K. R. Thioridazine: resurrection as an antimicrobial agent? // Br. J. Clin. Pharmacol. – 2007. – V. 64, N 5. – P. 566–574. http://doi.org/10.1111/j.1365-2125.2007.03021.x
15. Conte J. E., Barriere S. L. Manual of antibiotics and infectious diseases. – Philadelphia: Lea & Febiger, 1988.
16. Alsaad N., Wilffert B., van Altena R. et al. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis // Eur. Respiratory J. –2014. – V. 43. – P. 884–897. http://doi.org/10.1183/09031936.00113713
17. Amaral L., Molnar J. Mechanisms by which thioridazine in combination with antibiotics cures extensively drug-resistant infections of pulmonary tuberculosis // In Vivo. – 2014. – V. 28. – P. 267–272.
18. Martins M., Schelz Z., Martins A. et al. In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis // Int. J. Antimicrob. Agents. – 2007. – V. 29, N 3. – P. 338–340. http://doi.org/10.1016/j.ijantimicag.2006.10.013
19. Martins M., Viveiros M., Kristiansen J. E. et al. The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis // In Vivo. – 2007. – V. 21. – P. 771–775.
20. Ordway D., Viveiros M., Leandro C., et al. Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis // Antimicrob. Agents Chemother. – 2003. – V. 47. – P. 917–922. http://doi.org/10.1128/AAC.47.3.917-922.2003
21. Pieters J. Mycobacterium tuberculosis and the macrophage: maintaining a balance // Cell Host Microbe. – 2008. – V. 3, N 6. – P. 399407. http://doi.org/10.1016/j.chom.2008.05.006
22. Amaral L., Viveiros M. Thioridazine: a non-antibiotic drug highly effective, in combination with first line anti-tuberculosis drugs, against any form of antibiotic resistance of Mycobacterium tuberculosis due to its multi-mechanisms of action // Antibiotics (Basel). – 2017. – V. 6, N 1. http://doi.org/10.3390/antibiotics6010003
23. Weinstein E. A., Yano T., Li L. S. et al. Inhibitors of type II NADH: menaquinone oxidoreductase represent a class of antitubercular drugs // Proc. Natl. Acad. Sci. USA. – 2005. – V. 102. – P. 4548–4553. http://doi.org/10.1073/pnas.0500469102
24. Machado D., Couto I., Perdigão J. et al. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis // PLoS ONE. – 2012. – V. 7, N 4. http://doi.org/10.1371/journal.pone.0034538
25. Viveiros L., Amaral L. Enhancement of antibiotic activity against poly-drug resistant Mycobacterium tuberculosis by phenothiazines // Int. J. Antimicrob. Agents. – 2001. – V. 17, N 3. – P. 225228.
26. Ordway D., Viveiros M., Leandro C. et al. Intracellular activity of clinical concentrations of phenothiazines including thioridiazine against phagocytosed Staphylococcus aureus // Int. J. Antimicrob. Agents. – 2002. – V. 20. – P. 34–43. http://doi.org/10.1016/S0924-8579(02)00110-3
27. Kristiansen M. M., Leandro C., Ordway D. et al. Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro // Int. J. Antimicrob. Agents. – 2003. – V. 22. – P. 250–253. http://doi.org/10.1016/S0924-8579(03)00200-0
28. Martins M., Bleiss W., Marko A. et al. Clinical concentrations of thioridazine enhance the killing of intracellular methicillin-resistant Staphylococcus aureus: an in vivo, ex vivo and electron microscopy study // In Vivo. – 2004. – V. 18 – P. 787–794.
29. Hahn B. L., Sohnle P. G. Effect of thioridazine on experimental cutaneous staphylococcal infections // In Vivo. – 2014. – V. 28. – P. 3338.
30. Stenger M., Hendel K., Bollen P. et al. Assessments of thioridazine as a helper compound to dicloxacillin against methicillin-resistant Staphylococcus aureus: in vivo trials in a mouse peritonitis model // PLoS One. – 2015. – V. 10, N 8. http://doi.org/10.1371/journal.pone.0135571
31. Rivarola H. W., Paglini-Oliva P. A. Trypanosoma cruzi trypanothione reductase inhibitors: phenothiazines and related compounds modify experimental Chagas' disease evolution // Curr. Drug. Targets. Cardiovasc. Haematol. Disord. – 2002. V. 2. – P. 43–52. http://doi.org/10.2174/1568006023337745
32. Rivarola H. W., Fernandez A. R., Enders J. E. et al. Thioridazine treatment modifies the evolution of Trypanosoma cruzi infection in mice // Ann. Trop. Med. Parasitol. – 1999. – V. 93. – P. 695–702.
33. Bustamante J. M., Presti M. S., Rivarola H. W. et al. Treatment with benznidazole or thioridazine in the chronic phase of experimental Chagas disease improves cardiopathy // Int. J. Antimicrob. Agents. – 2007. – V. 29. – P. 733–737. http://doi.org/10.1016/j.ijantimicag.2007.01.014
34. Swarnkar P. K., Kriplani P., Gupta G. N. et al. Synthesis and antibacterial activity of some new phenothiazine derivatives // E-Journal of Chemistry. 2007. V. 4, N 1. – Р. 14– 20. http://doi.org/10.1155/2007/402673
35. Scalacci N., Brown A. K., Pavan F. R. et al. Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis // Inter. J. Antimicrobial Agents. 2017. V. 127. – Р. 147158. http://doi.org/10.1016/j.ejmech.2016.12.042
36. Takács D., Cerca P., Martins A. et al. Evaluation of forty new phenothiazine derivatives for activity against intrinsic efflux pump systems of reference Escherichia coli, Salmonella enteritidis, Enterococcus faecalis and Staphylococcus aureus strains // In Vivo. 2017. V. 25, N 5. – Р. 719724.
37. Kristiansen M. M., Leandro C., Ordway D. et al. Thioridazine reduces resistance of methicillin-resistant Staphylococcus aureus by inhibiting a reserpine-sensitive efflux pump // In Vivo. – 2006. – V. 20, N 3. – P. 361366.
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