Drug repositioning, a new alternative in infectious diseases

Serafin, Marissa Bolson; Hörner, Rosmari

doi:10.1016/j.bjid.2018.05.007

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Brazilian Journal of Infectious Diseases

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Letters to the Editor • Braz J Infect Dis 22 (3) • May-Jun 2018 • https://doi.org/10.1016/j.bjid.2018.05.007 copy

Drug repositioning, a new alternative in infectious diseases

Authorship SCIMAGO INSTITUTIONS RANKINGS

There has been a significant decrease in the number of approved antibiotics in the last two decades, and in parallel, a steady increase of multidrug resistant bacteria (MDR) has been occurring. Thus, MDR have become a global issue of public health, and with this threat, the challenge to develop new antibiotics has emerged in all areas: governmental, scientific, and the private pharmacological industry.¹[1] WHO/CDC/ICBDSR. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization; 2017. Available from: http://www.who.int/medicines/publications/global-prioritylist-antibiotic-resistant-bacteria/en/ [accessed 10.02.18].
http://www.who.int/medicines/publication... In this sense, drug repositioning has arisen as an alternative approach for the faster identification of drugs that are effective against infectious diseases.²[2] Zheng W, Sun W, Simeonov A. Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br J Pharmacol. 2018;175:181-91.

The expressions "Drug repositioning" and "drug repurposing" was first described by Ashburn and Thor (2004)³[3] Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673-83. in their paper "Drug repositioning: identifying and developing new uses for existing drugs". According to the authors, this is the process to find new uses for clinically approved drugs, and this is also known as redirecting and reprofiling.

Several studies have signalled that drug repositioning has advantages compared to the traditional way of seeking for active substances,²[2] Zheng W, Sun W, Simeonov A. Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br J Pharmacol. 2018;175:181-91.^,⁴[4] Mehndiratta MM, Wadhai SA, Tyagi BK, Gulati NS, Sinha M. Drugrepositioning. Int J Epilepsy. 2016;3:91-4.

[5] Papapetropoulos A, Szabo C. Inventing new therapies without reinventing the wheel: the power of drug repurposing. Br J Pharmacol. 2018;175:165-7.

[6] Thangamani S, Younis W, Seleem MN. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. Sci Rep. 2015;5:11596.^-⁷[7] Thangamani S, Younis W, Seleem MN. Repurposing clinical molecule ebselen to combat drug resistant pathogens. PLOS ONE. 2015;7:e0133877. since pharmacological, toxicological and bioavailability data, among others, are already available. Thus, less time is spent in their development, leading to a significant reduction in costs, and it proves to be a preferred and advantageous alternative strategy to discover drugs more quickly.⁴[4] Mehndiratta MM, Wadhai SA, Tyagi BK, Gulati NS, Sinha M. Drugrepositioning. Int J Epilepsy. 2016;3:91-4. Other encouraging data are the success rates for repositioned drugs, which are higher when compared to new drugs, reaching 30% in the last few years. Also, together with the positive aspects of repositioning is its recent approval by the Food and Drug Administration (FDA).⁸[8] Jin G, Wong S. Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today. 2014;19:637-44.

Comparing repurposing and use off-label, there is a similarity between these practices: a new indication of the drug, other than the usual one. However, the use outside the label goes beyond this, since it may include different age groups, dosage or route of administration. Although this is considered a legal and common application, it is often performed in the absence of adequate scientific data, and may expose patients to unrestricted and ineffective experimentation of drugs with unknown health risks.⁹[9] Gupta SK, Nayak RP. Off-label use of medicine: perspective of physicians, patients, pharmaceutical companies and regulatory authorities. J Pharmacol Pharmacother. 2014;5:88-92.

In Table 1, we present a summary of the repositioning of drugs for antibacterial treatment: examples of studies that investigate the antimicrobial activities of several pharmacological classes, including psychotropics, local anaesthetics, tranquilizers, cardiovascular drugs, antihistamines, anti-inflammatories, being these called "non-antibiotic drugs".¹⁰[10] Chan EWL, Yee ZY, Raja I, Yap JKY. Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant Staphylococcus aureus. J Glob Antimicrob Resist. 2017;10:70-4.

[11] Mandal A, Chandrima Sinha C, Jena AK, Ghosh S, Samanta A. An investigation on in vitro and in vivo antimicrobial properties of the antidepressant: amitriptyline hydrochloride. Braz J Microbiol. 2010;41:635-42.

[12] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9.

[13] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80.^-¹⁴[14] Rampelotto RF, Lorenzoni VV, Silva DC, et al. Synergistic antibacterial effect of statins with the complex {[1-(4-bromophenyl)-3-phenyltriazene N3-oxide-κ2 N1, O4](dimethylbenzylamine-κ2 C1, N4)palladium(II)}. Braz J Pharm Sci. 2018 [in press].

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Table 1
Studies of repositioning non-antibiotic drugs with antibiotic effect.

The treatment of chronic bacterial infections in immunocompromised patients with synergistic drug combinations is well established, and this procedure has been used for several years.¹⁵[15] Gonzáles PR, Pesesky MW, Bouley R, Ballard A, Biddy BA, Suckow MA. Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA. Nat Chem Biol. 2015;11:855-61. These synergistic combinations are used because of three main advantages: expansion of the antibiotic spectrum¹⁶[16] Ejim L, Afarha M, Falconer SB, et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011;7:348-50.^,¹⁷[17] Zilberberg MD, Shorr AF, Micek ST, Vazquez-Guillamet C, Kollef MH. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2014;18:596.; overcoming resistance¹⁸[18] Qin X, Tran BG, Kim MJ, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49:579-88.; and decrease of resistance to antibiotics through their careful use.¹⁹[19] Levin BR. Models for the spread of resistant pathogens. Neth J Med. 2002;60:58-64.

[20] Mahamat A, Mac Kenzie FM, Brooker K, Monnet DL, Daures JP, Gould IM. Impact of infection control interventions and antibiotic use on hospital MRSA: a multivariate interrupted time-series analysis. Int J Antimicrob Agents. 2007;30:169-76.^-²¹[21] Aldeyab MA, Monnet DL, Lopez-Lozano JM, et al. Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis. J Antimicrob Chemother. 2008;62:593-600.

Since repositioned non-antibiotic drugs have shown antibiotic effects among themselves as well as when used together with antimicrobials, these combinations presently consist of a useful option to overcome the problem of weak activity of individual drugs.²[2] Zheng W, Sun W, Simeonov A. Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br J Pharmacol. 2018;175:181-91.^,¹⁰[10] Chan EWL, Yee ZY, Raja I, Yap JKY. Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant Staphylococcus aureus. J Glob Antimicrob Resist. 2017;10:70-4.^,¹⁶[16] Ejim L, Afarha M, Falconer SB, et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011;7:348-50.

Based on the several studies presented, it can be inferred that the repositioning of non-antibiotic drugs with known toxicity profiles represents a promising alternative for the treatment of bacterial infections. Nevertheless, it is a consensus in the global scientific community that it is only the starting point, and additional studies regarding mechanisms of action and in vivo studies, among others, are vital for the safe use of these drugs.

References

^[1]
WHO/CDC/ICBDSR. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization; 2017. Available from: http://www.who.int/medicines/publications/global-prioritylist-antibiotic-resistant-bacteria/en/ [accessed 10.02.18].
» http://www.who.int/medicines/publications/global-prioritylist-antibiotic-resistant-bacteria/en/
^[2]
Zheng W, Sun W, Simeonov A. Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br J Pharmacol. 2018;175:181-91.
^[3]
Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673-83.
^[4]
Mehndiratta MM, Wadhai SA, Tyagi BK, Gulati NS, Sinha M. Drugrepositioning. Int J Epilepsy. 2016;3:91-4.
^[5]
Papapetropoulos A, Szabo C. Inventing new therapies without reinventing the wheel: the power of drug repurposing. Br J Pharmacol. 2018;175:165-7.
^[6]
Thangamani S, Younis W, Seleem MN. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. Sci Rep. 2015;5:11596.
^[7]
Thangamani S, Younis W, Seleem MN. Repurposing clinical molecule ebselen to combat drug resistant pathogens. PLOS ONE. 2015;7:e0133877.
^[8]
Jin G, Wong S. Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today. 2014;19:637-44.
^[9]
Gupta SK, Nayak RP. Off-label use of medicine: perspective of physicians, patients, pharmaceutical companies and regulatory authorities. J Pharmacol Pharmacother. 2014;5:88-92.
^[10]
Chan EWL, Yee ZY, Raja I, Yap JKY. Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant Staphylococcus aureus. J Glob Antimicrob Resist. 2017;10:70-4.
^[11]
Mandal A, Chandrima Sinha C, Jena AK, Ghosh S, Samanta A. An investigation on in vitro and in vivo antimicrobial properties of the antidepressant: amitriptyline hydrochloride. Braz J Microbiol. 2010;41:635-42.
^[12]
Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9.
^[13]
Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80.
^[14]
Rampelotto RF, Lorenzoni VV, Silva DC, et al. Synergistic antibacterial effect of statins with the complex {[1-(4-bromophenyl)-3-phenyltriazene N3-oxide-κ2 N1, O4](dimethylbenzylamine-κ2 C1, N4)palladium(II)}. Braz J Pharm Sci. 2018 [in press].
^[15]
Gonzáles PR, Pesesky MW, Bouley R, Ballard A, Biddy BA, Suckow MA. Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA. Nat Chem Biol. 2015;11:855-61.
^[16]
Ejim L, Afarha M, Falconer SB, et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011;7:348-50.
^[17]
Zilberberg MD, Shorr AF, Micek ST, Vazquez-Guillamet C, Kollef MH. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2014;18:596.
^[18]
Qin X, Tran BG, Kim MJ, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49:579-88.
^[19]
Levin BR. Models for the spread of resistant pathogens. Neth J Med. 2002;60:58-64.
^[20]
Mahamat A, Mac Kenzie FM, Brooker K, Monnet DL, Daures JP, Gould IM. Impact of infection control interventions and antibiotic use on hospital MRSA: a multivariate interrupted time-series analysis. Int J Antimicrob Agents. 2007;30:169-76.
^[21]
Aldeyab MA, Monnet DL, Lopez-Lozano JM, et al. Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis. J Antimicrob Chemother. 2008;62:593-600.
^[22]
Muthukumar V, Janakiraman K. Evaluation of antibacterial activity of amitriptyline hydrochloride. Int J Chem Tech Res. 2014;6:4878-83.
^[23]
Harbut MB, Vilchèze C, Luo X, et al. Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. PNAS. 2015;112:4453-8.
^[24]
Naylor S, Schonfeld JM. Therapeutic drug repurposing, repositioning and rescue. Drug Discov World Winter. 2014;:49-62.
^[25]
Phillips M, Malloy G, Nedunchezian D, Lukrec A, Howard RG. Disulfiram inhibits the in vitro growth of methicillin-resistant Staphylococcus aureus Antimicrob Agents Chemother. 1991;35:785-7.
^[26]
Velasco-García RV, Zaldívar-Machorro VJ, Carlos Mújica-Jiménez CM, González-Segura L, Muñoz-Clares RA. Disulfiram irreversibly aggregates betaine aldehyde dehydrogenase - a potential target for antimicrobial agents against Pseudomonas aeruginosa Biochem Biophys Res Commun. 2006;341:408-15.
^[27]
Akilandeswari K, Ruckmani K, Ranjith MV. Efficacy of antibacterial activity of antibiotics ciprofloxacin and gentamycin improved with anti depressant drug, Escitalopram. Int J Pharm Sci Rev Res. 2013;21:71-4.
^[28]
López-Muñoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm. 2009;:1563-86.
^[29]
Samanta A, Chattopadhyay D, Sinha C, Jana AD, Ghosh S, Banerjee AMA. Evaluation of in vivo and in vitro antimicrobial activities of a selective serotonin reuptake inhibitor sertraline hydrochloride. Anti-Infective Agents. 2012;10.
^[30]
Graziano TS, Cuzzullin MC, Franco GC, et al. Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm. PLOS ONE. 2015, http://dx.doi.org/10.1371/journal.pone.0128098
» http://dx.doi.org/10.1371/journal.pone.0128098
^[31]
Paravar T, Lee DJ. Thalidomide: mechanisms of action. Int Rev Immunol. 2008;27:111-35.

Publication Dates

Publication in this collection
May-Jun 2018

History

Received
5 Apr 2018
Published
28 June 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivative License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the original work is properly cited and the work is not changed in any way.

Drug	Original indication	New indication	Reference
AAS	Non-steroidal Anti-inflammatory	MRSA	Chan et al., 2017¹⁰[10] Chan EWL, Yee ZY, Raja I, Yap JKY. Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant Staphylococcus aureus. J Glob Antimicrob Resist. 2017;10:70-4.
Amitriptiline	Antidepressant	Staphylococcus spp. Enterococcus faecalis Micrococcus luteus Bacillus spp. Shigella spp. Salmonella spp. Vibrio cholerae Vibrio parahaemolyticus Escherichia coli Klebsiella pneumonia Pseudomonas spp. Proteus spp. Citrobacter spp. Providencia spp. Enterobacter cloacae Hafnia spp. Lactobacillus sporogenes Micrococcus flavus Vibrio cholerae	Mandal et al., 2010¹¹[11] Mandal A, Chandrima Sinha C, Jena AK, Ghosh S, Samanta A. An investigation on in vitro and in vivo antimicrobial properties of the antidepressant: amitriptyline hydrochloride. Braz J Microbiol. 2010;41:635-42. Muthukumar and Janakiraman, 2014²²[22] Muthukumar V, Janakiraman K. Evaluation of antibacterial activity of amitriptyline hydrochloride. Int J Chem Tech Res. 2014;6:4878-83.
Auranofin	Rheumatoidarthritis	MRSA	Harbut et al., 2015²³[23] Harbut MB, Vilchèze C, Luo X, et al. Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. PNAS. 2015;112:4453-8.
Chlorpromazine	Anti-psychotic	Corynebacterium urealyticum Escherichia coli Klebsiella pneumoniae Citrobacter freundii Morganella morganii Acinetobacter baumannii Haemophilus influenzae Moraxella catarrhalis Campylobacter jejuni Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Streptococcus agalactiae Enterococcus faecalis Clostridium perfringens Clostridium difficile Bacreroides fragilis Prevotella spp. Brucella spp.	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 1996¹²[12] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9. Munoz-Bellido, Munoz-Criado and García-Rodríguez, 2000¹³[13] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80.
Clofazime	Tuberculosis	Mycobacterium leprae	Naylorand Schonfeld, 2014²⁴[24] Naylor S, Schonfeld JM. Therapeutic drug repurposing, repositioning and rescue. Drug Discov World Winter. 2014;:49-62.
Clomipramine	Antidepressant	Serratia marcescens Morganella morganii Acinetobacter baumannii Haemophilus influenza Campylobacter jejuni Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Streptococcus agalactiae Enterococcus faecalis Clostridium perfringens Clostridium difficile Bacteroides fragilis Prevotella spp. Brucella spp.	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 2000¹³
Disulfiram	Alcoholism	MRSA Pseudomonas aeruginosa	Phillips et al., 1991²⁵[25] Phillips M, Malloy G, Nedunchezian D, Lukrec A, Howard RG. Disulfiram inhibits the in vitro growth of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1991;35:785-7. Velasco-García et al., 2006²⁶[26] Velasco-García RV, Zaldívar-Machorro VJ, Carlos Mújica-Jiménez CM, González-Segura L, Muñoz-Clares RA. Disulfiram irreversibly aggregates betaine aldehyde dehydrogenase - a potential target for antimicrobial agents against Pseudomonas aeruginosa. Biochem Biophys Res Commun. 2006;341:408-15.
Ebselen	Neuroprotector	MRSA VRSA Streptococcus spp. Enterococcus spp.	Thangamani, Younis e Seleem 2015⁶[6] Thangamani S, Younis W, Seleem MN. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. Sci Rep. 2015;5:11596.^,⁷[7] Thangamani S, Younis W, Seleem MN. Repurposing clinical molecule ebselen to combat drug resistant pathogens. PLOS ONE. 2015;7:e0133877.
Escitalopram	Antidepressant	Klebsiella pneumoniae Proteus mirabilis Enterobactor cloacae Staphylococcus aureus Pseudomonas aeruginosa	Akilandeswari, Ruckmani and Ranjith, 2013²⁷[27] Akilandeswari K, Ruckmani K, Ranjith MV. Efficacy of antibacterial activity of antibiotics ciprofloxacin and gentamycin improved with anti depressant drug, Escitalopram. Int J Pharm Sci Rev Res. 2013;21:71-4.
Fluoxetine	Antidepressant	Corynebacterium urealyticum Haemophilus influenzae Moraxella catarrhales Campylobacter jejuni	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 1996¹²[12] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9. Munoz-Bellido, Munoz-Criado and García-Rodríguez, 2000¹³[13] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80.
Ibuprofen	Non-steroidalAnti-inflammatory	MRSA	Chan et al., 2017¹⁰[10] Chan EWL, Yee ZY, Raja I, Yap JKY. Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant Staphylococcus aureus. J Glob Antimicrob Resist. 2017;10:70-4.
Iproniazid	Antidepressant	Mycobacterium tuberculosis	López-Muñoz and Alamo, 2009²⁸[28] López-Muñoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm. 2009;:1563-86.
Loperamide	Diarrhoea	Salmonella enterica	Ejim et al., 2011¹⁶[16] Ejim L, Afarha M, Falconer SB, et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011;7:348-50.
Sertraline	Antidepressant	Corynebacterium urealyticum Escherichia coli Klebsiella pneumoniae Enterococcus cloacae Citrobacter freundii Serratia marcescens Proteus mirabilis Proteus vulgaris Morganella morganii Acinetobacter baumannii Haemophilus influenzae Moraxella catarrhalis Campylobacter jejuni Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Streptococcus agalactiae Enterococcus faecalis Clostridium perfringens Clostridium difficile Bacteroides fragilis Prevotella spp. Brucella spp. Staphylococcus spp. Micrococcus luteus Bacillus subtilis Shigella spp. Salmonella spp. Vibrio cholerae Vibrio parahaemolyticus Pseudomonas aeruginosa Providencia spp. Lactobacillus sporogenes	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 1996¹²[12] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9. Munoz-Bellido, Munoz-Criado and García-Rodríguez, 2000¹³[13] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80. Samanta et al., 2012²⁹[29] Samanta A, Chattopadhyay D, Sinha C, Jana AD, Ghosh S, Banerjee AMA. Evaluation of in vivo and in vitro antimicrobial activities of a selective serotonin reuptake inhibitor sertraline hydrochloride. Anti-Infective Agents. 2012;10.
Paroxetine	Antidepressant	Corynebacterium urealyticum Haemophilus influenzae Moraxella catarrhales Campylobacter jejuni	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 1996¹²[12] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9. Munoz-Bellido, Munoz-Criado and García-Rodríguez, 2000¹³[13] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80.
Risperidone	Anti-psychotic	Corynebacterium urealyticum	Munoz-Bellido, Munoz-Criado and García-Rodríguez, 1996¹²[12] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2). J Antimicrob Chemother. 1996;37:1005-9. Munoz-Bellido, Munoz-Criado and García-Rodríguez, 2000¹³[13] Munoz-Bellido JL, Munoz-Criado S, García-Rodríguez JA. Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14:177-80.
Simvastatin and Atorvastatin	Cardiovascular diseases	Staphylococcus epidermidis Staphylococcus aureus Salmonella spp. Pseudomonas aeruginosa Micrococcus luteus Klebsiella pneumoniae Escherichia coli Enterococcus faecalis Enterobacter hormaechei Bacillus cereus Staphylococcus spp. Staphylococcus coagulase negative MRSA	Rampelotto et al., 2018 in press¹⁴[14] Rampelotto RF, Lorenzoni VV, Silva DC, et al. Synergistic antibacterial effect of statins with the complex {[1-(4-bromophenyl)-3-phenyltriazene N3-oxide-κ2 N1, O4](dimethylbenzylamine-κ2 C1, N4)palladium(II)}. Braz J Pharm Sci. 2018 [in press]. Graziano et al., 2015³⁰[30] Graziano TS, Cuzzullin MC, Franco GC, et al. Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm. PLOS ONE. 2015, http://dx.doi.org/10.1371/journal.pone.0128098. http://dx.doi.org/10.1371/journal.pone.0...
Thalidomide	Anti-nausea	Mycobacterium leprae	Paravar and Lee, 2008³¹[31] Paravar T, Lee DJ. Thalidomide: mechanisms of action. Int Rev Immunol. 2008;27:111-35.

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Acompanhe os números deste periódico no seu leitor de RSS

[1] ^[1]
WHO/CDC/ICBDSR. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization; 2017. Available from: http://www.who.int/medicines/publications/global-prioritylist-antibiotic-resistant-bacteria/en/ [accessed 10.02.18].
» http://www.who.int/medicines/publications/global-prioritylist-antibiotic-resistant-bacteria/en/

[2] ^[2]
Zheng W, Sun W, Simeonov A. Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br J Pharmacol. 2018;175:181-91.

[3] ^[3]
Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673-83.

[4] ^[4]
Mehndiratta MM, Wadhai SA, Tyagi BK, Gulati NS, Sinha M. Drugrepositioning. Int J Epilepsy. 2016;3:91-4.

[5] ^[5]
Papapetropoulos A, Szabo C. Inventing new therapies without reinventing the wheel: the power of drug repurposing. Br J Pharmacol. 2018;175:165-7.

[6] ^[6]
Thangamani S, Younis W, Seleem MN. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. Sci Rep. 2015;5:11596.

[7] ^[7]
Thangamani S, Younis W, Seleem MN. Repurposing clinical molecule ebselen to combat drug resistant pathogens. PLOS ONE. 2015;7:e0133877.

[8] ^[8]
Jin G, Wong S. Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today. 2014;19:637-44.

[9] ^[9]
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