Abstract
In the present study we evaluated the biological activity of amitriptyline, a tricyclic antidepressant, and its antibacterial activity was determined in vitro, individually and in combination with ciprofloxacin, sulfamethoxazole-trimethoprim, and colistin. Being tested against multi drug resistant clinical isolates and American Type Culture Collection (ATCC) standard strains, through the fractional inhibitory concentration index (FICI) and tolerance index. Their ability to cleave plasmid DNA was also analyzed. Amitriptyline showed activity against Gram-positive and Gram-negative bacteria. In combination with colistin, two strains of Klebsiella pneumoniae producing carbepenemase with a minimum inhibitory concentration of 4 μg/mL were prominent. FICI demonstrated synergistic effect in 15 combinations with antibiotics. Amitriptyline was able to cleave the DNA at concentrations of 3.75 and 1.875 mM at pH 7.4 at 50 °C. The results obtained in this study allow us to suggest amitriptyline as a potential antibiotic in drug repositioning.
Similar content being viewed by others
References
Abd-El-Aziz AS, Agatemor C, Etkin N (2017) Antimicrobial resistance challenged with metal-based antimicrobial macromolecules. Biomaterials 118:27–50. https://doi.org/10.1016/j.biomaterials.2016.12.002
Annadurai S, Basu S, Ray S, Dastidar SG, Chakrabarty NA (1998) Antibacterial activity of the anti-inflammatory agente diclofenac sodium. Indian J Exp Biol 36:86–90
Ashburn TT, Thor KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683. https://doi.org/10.1038/nrd1468
AsokKumar K, Ganguly K, Mazumdar K, Dutta NK, Dastidar SG, Chakrabarty NA (2003) Amlodipine: a cardiovascular drug with power ful antimicrobial property. Acta Microbiol Pol 52:285–292
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (2003) Current protocols in molecular biology. 5th edn. John Wiley & Sons Inc., Hoboken, NJ, USA; ISBN: 978-0.471-50338-5
Bielecka-Wajdman AM, Ludyga T, Machnik G, Gołyszny M, Obuchowicz E (2018) Tricyclic antidepressants modulate stressed mitochondria in glioblastoma multiforme cells. Cancer Control 25:1–9. https://doi.org/10.1177/1073274818798594
Brown D (2015) Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? Nat Rev Drug Discov 14:821–832. https://doi.org/10.1038/nrd4675
CLSI (2018). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 11th edn. CLSI standard M07. Clinical and Laboratory Institute, Wayne, PA. ISBN: 1-56238-836-3
Chakrabarty AN, Acharya DP, Niyogi D, Dastidar SG (1989) Drug interaction of some non conventional antimicrobial chemotherapeutic agentes with special reference to promethazine. Indian J Med Res 89:233–237
Das B, Mandal D, Dash SK, Chattopadhyay S, Tripathy S, Dolai DP, Dey SK, Roy S (2016) Eugenol provokes ROS-mediated membrane damage-associated antibacterial activity against clinically isolated multidrug-resistant Staphylococcus aureus strains. Infect Dis 9:11–19. https://doi.org/10.4137/IDRT.S31741
Dastidar SG, Saha PK, Sanyamat B, Chakrabarty AN (1976) Antibacterial activities of ambodryl and benadryl. J Appl Bacteriol 41:209–214. https://doi.org/10.1111/j.1365-2672.1976.tb00621.x
Dastidar SG, Mondal U, Niyogi S, Chakrabaty NA (1986) Antibacterial property of methyl-DOPA and development of cross resistance in m-DOPA mutants. Indian J Med Res 84:142–147
Dastidar SG, Das S, Mookerjee M, Chattopadhyay D, Ray S, Chakrabarty AN (1988) Antibacterial activity of local anaesthetics procaine and lignocaine. Indian J Med Res 87:506–508
Dastidar SG, Chaudhuri A, Annadurai S, Ray S, Mookherjee M, Chakrabarty AN (1995) In vitro and in vivo antimicrobial action of fluphenazine. J Chemother 7:201–206. https://doi.org/10.1179/joc.1995.7.3.201
Duarte EH, Gorla FA, Sartori ER, Tarley CRT (2014) Voltammetric determination of amitriptyline in pharmaceutical formulations with boron doped diamond electrode exploiting measurements in acid medium. Mod Chem 37:1496–1502. https://doi.org/10.5935/0100-4042.20140225
Ejim L, Farha MA, Falconer SB, Wildenhain J, Coombes BK, Tyers M, Brown ED, Wright GD (2011) Combinations of antibiotics and non antibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 7:348–350. https://doi.org/10.1038/nchembio.559
Gowda KRS, Mathew BB, Sudhamani CN, Naik HSB (2014) Mechanism of DNA binding and cleavage. J Biomed Biotechnol 2:1–9. https://doi.org/10.12691/bb-2-1-1
Federico MP, Furtado GH (2018) Immediate and later impacts of antimicrobial consumption on carbapenem-resistant Acinetobacter spp., Pseudomonas aeruginosa, and Klebsiella spp. in a teaching hospital in Brazil: a 10-year trend study. Eur J Clin Microbiol Infect Dis 37:2153–2158. https://doi.org/10.1007/s10096-018-3352-1
Konaté K, Movoungou JF, Lepengué AN, Aworet-Samseny RRR, Hilou A, Souza A, Dicko MH, M’Batchi B (2012) Antibacterial activity against β- lactamase producing Methicillin and Ampicillin-resistants Staphylococcus aureus: fractional Inhibitory Concentration Index (FICI) determination. Ann Clin Microbiol Antimicrob 11:18. https://doi.org/10.1186/1476-0711-11-18
Kristiansen JE, Amaral L (1997) The potential management of resistant infections with non-antibiotics. J Antimicrob Chemother 40:319–327. https://doi.org/10.1093/jac/40.3.319
Kristiansen JE, Blom J (1981) Effect of chlorpromazine on the ultra structure of Staphylococcus aureus. Acta Pathol Microbiol Scand, Sect B: Microbiol 89:399–405. PMID: 7336926
Loureiro RJ, Roque F, Rodrigues AT, Herdeiro MT, Ramalheira E (2016) O uso de antibióticos e as resistências bacterianas: breves notas sobre a sua evolução. Rev Port Sau Pub 34:77–84. https://doi.org/10.1016/j.rpsp.2015.11.003
Mandal A, Sinha C, Jena AK, Ghosh S, Samanta A (2010) An investigation on in vitro and in vivo antimicrobial properties of the antidepressant: amitriptyline hydrochloride. Braz J Microbiol 41:635–642. https://doi.org/10.1590/S1517-83822010000300014
Manna KK, Dastidar SG (1984) The anti-hypertensive drug propranolol hydrochloride (carditap): its anti-bacterial property. In: Proceedings of the 6th national congress of the Indian Association of Medical Microbiologists (IAMM). pp 137–141
Moraes FLL (2012) Evaluation of antidepressants as anadjuvant in the treatment of cancer pain. [Completion of course work]. Paraiba: State University of Paraiba, Center for Biological and Health Sciences.
Morehead MS, Scarbrough C (2018) Emergence of global antibiotic resistance. Prim Care 45:467–484. https://doi.org/10.1016/j.pop.2018.05.006
Mustaev A, Malik M, Zhao X, Kurepina N, Luan G, Oppegard LM, Hiasa H, Marks KR, Kerns RJ, Berger JM, Drlica K (2014) Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding. J Biol Chem 289:12300–12312. https://doi.org/10.1074/jbc.M113.529164
Muthukumar V, Janakiraman K (2014) Evoluation of antibacterial activy of amitriptyline hydrochloride. Int J ChemTech Res 6:4878–4883
National Committee for Clinical Laboratory Standards (1999) Methods for determining bactericidal activity of antimicrobial agents. Approved Guideline M26-A. vol. 19; No. 8. NCCLS, Wayne, USA. https://clsi.org/media/1462/m26a_sample.pdf
Naeem A, Badshah SL, Muska M, Ahmad N, Khan K (2016) The current case of quinolones: synthetic approaches and antibacterial activity. Molecules 21:268. https://doi.org/10.3390/molecules21040268
Odds FC (2003) Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 52:1–1. https://doi.org/10.1093/jac/dkg301
Olaitan AO, Morand S, Rolain JM (2016) Emergence of colistin-resistant bacteria in humans without colistin usage: a new worry and cause for vigilance. Int J Antimicrob Agents 47:1–3. https://doi.org/10.1016/j.ijantimicag.2015.11.009
Pal T, Dutta NK, Mazumder K, Dasgupta A, Jeyaseeli L, Dastidar SG (2006) Assesement of antibacterial activity of the cardiovascular drug Nifedipine. Orient Pharm Exp Med 6:126–133. https://doi.org/10.3742/OPEM.2006.6.2.126
Palit PP, Mandal SC, Mandal NB (2013) Reuse of old, existing, marketed non-antibiotic drugs as antimicrobial agents: a new emerging therapeutic approach. In: A Méndez-Vilas (ed) Microbial pathogens and strategies for combating them: science, technology and education, Spain: Badajoz: Formatex Research Center. p 1883–1892
Pelógia NCC, Machado BG, Almeida FCB, Constantino E, Pires OC (2011) Amitriptyline effects on acutepa in modulation in rats submitted to sciatic nerve ligation. J Pain 12:245–249. https://doi.org/10.1590/S1806-00132011000300010
Pitout JDD, Nordmann P, Poirel L (2015) Carbapenemase-producing Klebsiella pneumoniae, akey pathogen set for global nosocomial dominance. Antimicrob Agents Chemother 59:5873–5884. https://doi.org/10.1128/AAC.01019-15
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doing A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M (2018) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18:41–58. https://doi.org/10.1038/nrd.2018.168
Rang & Dale Farmacologia (2012) 7edn. Elsevier, Rio de Janeiro, RJ XXV, 778p
Rodrigues SA Chlorpromazine, C17H19N2SCl. Modern Chemistry. http://qnint.sbq.org.br/novo/index.php?hash=molecula.264 Accessed July 2019
Santiago MDS, Carvalho DS, Gabbai AA, Pinto MMP, Moutran ARC, Villa TR (2014) Amitriptyline and aerobic exercise or amitriptyline alone in the treatment of chronic migraine: a randomized comparative study. Arch Neuro-Psychiatry 72:851–855. https://doi.org/10.1590/0004-282X20140148
Sarkar A, Kumar KA, Dutta NK, Chakraborty P, Dastidar SG (2003) Evaluation of in vitro and in vivo antibacterial activity of dobutamine hydrochloride. Indian J Med Microbiol 21:172–178
Schneider EK, Reyes-Ortega F, Velkov T, Li J (2017) Antibiotic–non-antibiotic combinations for combating extremely drug-resistant Gram-negative “superbugs”. Essays Biochem 61:115–125. https://doi.org/10.1042/EBC20160058
Serafin MB, Hörner R (2018) Drug repositioning, a new alternative in infectious diseases. Braz J Infect Dis 22:252–256. https://doi.org/10.1016/j.bjid.2018.05.007
Silva RF (2010) Fungal infections in immunocompromised animals. J Bras Pneumol São Paulo, 36(1):142–147 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1806-37132010000100019&lng=en&nrm=iso. https://doi.org/10.1590/S1806-37132010000100019 Accessed 19 July 2019
Xue H, Li J, Xie H, Wang Y (2018) Review of drug repositioning approaches and resources. Int J Biol Sci 14:1232–1244. https://doi.org/10.7150/ijbs.24612
Zawacka K, Love W, Lanzas C, Booth JG, Gröhn YT (2018) Inferring the interaction structure of resistance to antimicrobials. Prev Vet Med 152:81–88. https://doi.org/10.1016/j.prevetmed.2018.02.007
Yeo CY, Sim JH, Khoo CH, Goh ZJ, Ang KP, Cheah YK, Fairuz ZA, SNBA Halim, Ng SW, Seng HL, Tiekink ERT (2013) Pathogenic Gram-positive bacteria are highly sensitive to triphenylphosphanegold(O-alkylthiocarbamates), Ph3PAu[SC(OR)=N(p-tolyl)] (R = Me, Et and iPr). Gold Bull 46:145–152. https://doi.org/10.1007/s13404-013-0091-z
Acknowledgements
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
de S. Machado, C., da Rosa, T.F., Serafin, M.B. et al. In vitro evaluation of the antibacterial activity of amitriptyline and its synergistic effect with ciprofloxacin, sulfamethoxazole–trimethoprim, and colistin as an alternative in drug repositioning. Med Chem Res 29, 166–177 (2020). https://doi.org/10.1007/s00044-019-02470-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-019-02470-x