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Reposicionamento de fármacos para diminuição da resistência mediada por bombas de efluxo em Neisseria gonorrhoeae e outras bactérias Gram-negativas
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Neisseria gonorrhoeae é o agente etiológico da gonorreia, uma infeção sexualmente
transmissível (IST). Em 2020, de acordo com a Organização Mundial da Saúde (OMS),
registaram-se 82 milhões de novos casos de gonorreia, com uma taxa global de incidência
de 19/1000 mulheres e de 23/1000 homens. Ao longo dos últimos 87 anos, introduziram se vários antibióticos no combate a esta IST, nomeadamente as sulfonamidas, penicilina,
tetraciclina, espectinomicina, ciprofloxacina, azitromicina, ceftriaxona e cefixima.
Contudo, observou-se a emergência de diferentes mecanismos de resistência aos
antimicrobianos que incluem: alterações na permeabilidade da parede celular; degradação
enzimática; modificação do alvo; e extrusão do fármaco através de bombas de efluxo.
Atualmente, o tratamento recomendado para a gonorreia não complicada consiste na
utilização de uma cefalosporina de 3ª geração (cefixima ou ceftriaxona) em monoterapia,
ou em combinação com azitromicina. No entanto, já foram descritos casos de falha
terapêutica, sendo crucial o desenvolvimento de novos fármacos para o tratamento destas
infeções.
Nesta Dissertação, avaliou-se a atividade dos seguintes compostos, candidatos a
reposicionamento contra N. gonorrhoeae: ácido deoxicólico, clomipramina,
deferoxamina, dequalínio, desipramina, duloxetina e procainamida. Estes compostos
apresentam transportadores de membrana (incluindo bombas de efluxo) como potenciais
alvos em N. gonorrhoeae.
Para avaliar a potencial atividade inibitória de efluxo dos compostos estudados, utilizou se um sistema modelo em Escherichia coli. Posteriormente, determinou-se a sua atividade
antimicrobiana e o seu potencial efeito adjuvante da atividade de antibióticos em N.
gonorrhoeae. Verificou-se que a clomipramina, o dequalínio, a desipramina e a
duloxetina foram os compostos que apresentaram valores de CMI mais baixos para a
estirpe de referência e isolados clínicos de N. gonorrhoeae. Estes quatro composto, em
conjunto com o ácido deoxicólico e a deferoxamina, promoveram a ação de antibióticos
em N. gonorrhoeae. Por fim, a clomipramina e o dequalínio demonstraram atividade
inibitória de efluxo significativa.
Em conclusão, os compostos mais promissores identificados neste trabalho deverão
continuar a ser estudados, nomeadamente no desenvolvimento de derivados com
potencial para futuras opções terapêuticas para o tratamento da gonorreia
Neisseria gonorrhoeae is the etiological agent of gonorrhoea, a sexually transmitted infection (STI). In 2020, according to the World Health Organization (WHO), 82 million new cases of gonorrhoea were registered, with a global incidence rate of 19/1000 women and 23/1000 men. Over the last 87 years, several antibiotics were introduced in the fight against this STI, namely sulphonamides, penicillin, tetracycline, spectinomycin, ciprofloxacin, azithromycin, ceftriaxone and cefixime. However, several antimicrobial resistance mechanisms emerged, which include; alterations in cell wall permeability; enzymatic degradation; target modification; and drug extrusion by efflux pumps. Currently, the commended treatment for uncomplicated gonorrhoea consists of 3rd generation cephalosporins (cefixime or ceftriaxone) in monotherapy, or in combination with azithromycin. However, there have already been reported cases of treatment failure, and thus it is crucial to develop new drugs to treat these infections. In this Dissertation, we evaluated the activity of the following compounds, potential candidates for repositioning against N. gonorrhoeae: deoxycholic acid, clomipramine, deferoxamine, dequalinium, desipramine, duloxetine and procainamide. These compounds present membrane transporters (including efflux pumps) as potential targets in N. gonorrhoeae. To evaluate the potential efflux inhibition activity of the studied compounds, we used a model system in Escherichia coli. Subsequently, we determined their antimicrobial activity and potential adjuvant effect of the activity of antibiotics in N. gonorrhoeae. We found that clomipramine, dequalinium, desipramine and duloxetine were the compounds that presented lower MIC values for the reference strain and clinical isolates of N. gonorrhoeae. These four compounds, together with deoxycholic acid and deferoxamine, promoted the activity of antibiotics in N. gonorrhoeae. Finally, clomipramine and dequalinium showed significant efflux inhibition activity. In conclusion, the most promising compounds identified in this work should be further studied, namely in the development of derivates with potential for future therapeutic options for gonorrhoea treatment.
Neisseria gonorrhoeae is the etiological agent of gonorrhoea, a sexually transmitted infection (STI). In 2020, according to the World Health Organization (WHO), 82 million new cases of gonorrhoea were registered, with a global incidence rate of 19/1000 women and 23/1000 men. Over the last 87 years, several antibiotics were introduced in the fight against this STI, namely sulphonamides, penicillin, tetracycline, spectinomycin, ciprofloxacin, azithromycin, ceftriaxone and cefixime. However, several antimicrobial resistance mechanisms emerged, which include; alterations in cell wall permeability; enzymatic degradation; target modification; and drug extrusion by efflux pumps. Currently, the commended treatment for uncomplicated gonorrhoea consists of 3rd generation cephalosporins (cefixime or ceftriaxone) in monotherapy, or in combination with azithromycin. However, there have already been reported cases of treatment failure, and thus it is crucial to develop new drugs to treat these infections. In this Dissertation, we evaluated the activity of the following compounds, potential candidates for repositioning against N. gonorrhoeae: deoxycholic acid, clomipramine, deferoxamine, dequalinium, desipramine, duloxetine and procainamide. These compounds present membrane transporters (including efflux pumps) as potential targets in N. gonorrhoeae. To evaluate the potential efflux inhibition activity of the studied compounds, we used a model system in Escherichia coli. Subsequently, we determined their antimicrobial activity and potential adjuvant effect of the activity of antibiotics in N. gonorrhoeae. We found that clomipramine, dequalinium, desipramine and duloxetine were the compounds that presented lower MIC values for the reference strain and clinical isolates of N. gonorrhoeae. These four compounds, together with deoxycholic acid and deferoxamine, promoted the activity of antibiotics in N. gonorrhoeae. Finally, clomipramine and dequalinium showed significant efflux inhibition activity. In conclusion, the most promising compounds identified in this work should be further studied, namely in the development of derivates with potential for future therapeutic options for gonorrhoea treatment.
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Palavras-chave
Microbiologia médica Doenças sexualmente transmitidas Neisseria gonorrhoeae Gonorreia Mecanismos de resistência Bombas de efluxo Reposicionamentos de fármacos Biologia molecular Saúde tropical e internacional-saúde pública