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Publicação
Estudo da atividade antimicrobiana de derivados de Azauronas e Sphaerococcenol A
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Resumo(s)
A tuberculose (TB) continua a ser uma das doenças provocadas por um único agente infecioso que mais
morbilidade e mortalidade causa a nível mundial. Porém, os tratamentos existentes são longos e nem
sempre eficazes, promovendo a emergência e incidência de estirpes resistentes, sendo cada vez mais
importante a descoberta e utilização de novas terapias para o combate desta patologia. Este trabalho tem,
então, como objetivo determinar se os derivados de azauronas e de sphaerococcenol A são possíveis
alternativas terapêuticas para a TB. Relativamente aos derivados de azauronas, estes foram
identificados, através de ensaios de microdiluição, como ativos apenas contra micobactérias
tuberculosas pertencentes ao complexo Mycobacterium tuberculosis (MTBC), sendo que essa atividade
contra Mycobacterium tuberculosis (Mtb) é bacteriostática. Para além disto, apesar destes fármacos
serem aparentemente tóxicos (índice de seletividade < 1), eles apresentam sinergia com macrófagos
diferenciados de células THP-1. Contudo, o mecanismo de ação destes derivados continua por
determinar, apesar de não parecer envolver bombas de efluxo inibidas por reserpina e clorpromazina. Já
os derivados de sphaerococcenol A não apresentam atividade contra Mtb, mas sim contra M. smegmatis
e contra uma variada gama de bactérias de Gram-positivo com diferentes graus de resistências a outros
antibióticos. Estas atividades são, contudo, diferentes, visto que para a micobactéria não-tuberculosa de
crescimento rápido a atividade é bactericida e que para as bactérias de Gram-positivo é bacteriostática,
promovendo para estas últimas um fenómeno de tolerância. Adicionalmente, determinou-se que a
eficácia destes fármacos depende da presença do grupo hidroxilo à frente do plano em vez de um grupo
carbonilo. Logo, apesar de só os derivados de azauronas serem promissores para o tratamento da TB, os
derivados de sphaerococcenol A são promissores para o combate a infeções provocadas por bactérias
de Gram-positivo, pelo que se está perante fármacos importantes para o combate a duas ameaças de
saúde pública.
Tuberculosis (TB), caused by a single infectious agent, continues to be one of the diseases with more morbidity and mortality worldwide. However, existing treatments are long and not always effective, promoting the emergence and incidence of resistant strains, so it is extremely important to discover and use new therapies to fight against this pathology. Hence, the objective of this study is to determine whether azaaurone and sphaerococcenol A derivatives are possible therapeutic alternatives for TB. Regarding azaaurone derivatives, they have been identified, through microdilution assays, as active only against tuberculous mycobacteria belonging to the Mycobacterium tuberculosis complex (MTBC), and they have a bacteriostatic activity against Mycobacterium tuberculosis (Mtb). Furthermore, although these drugs are apparently toxic (selectivity index < 1), they have synergy with differentiated macrophages of THP-1 cells. But the mechanism of action of these derivatives remains to be determined, although it does not appear to involve efflux pumps inhibited by reserpine and chlorpromazine. On the other hand, sphaerococcenol derivatives do not show activity against Mtb, but against M. smegmatis and against a wide range of Gram-positive bacteria with different degrees of resistance to other antibiotics. Nevertheless, these activities are different, since for the fast-growing nontuberculous Mycobacterium the activity is bactericidal and for the Gram-positive bacteria it is bacteriostatic, which promotes a tolerance phenomenon for these last bacteria. In addition, it has been determined that the efficacy of these derivatives depends on the presence of the hydroxyl group ahead of the plane rather than a carbonyl group. Therefore, although only azaaurone derivatives are promising drugs for the treatment of TB, sphaerococcenol A derivatives are promising drugs for the therapy of infections caused by Grampositive bacteria, thus these two groups of derivatives are important to fight against two threats to global health.
Tuberculosis (TB), caused by a single infectious agent, continues to be one of the diseases with more morbidity and mortality worldwide. However, existing treatments are long and not always effective, promoting the emergence and incidence of resistant strains, so it is extremely important to discover and use new therapies to fight against this pathology. Hence, the objective of this study is to determine whether azaaurone and sphaerococcenol A derivatives are possible therapeutic alternatives for TB. Regarding azaaurone derivatives, they have been identified, through microdilution assays, as active only against tuberculous mycobacteria belonging to the Mycobacterium tuberculosis complex (MTBC), and they have a bacteriostatic activity against Mycobacterium tuberculosis (Mtb). Furthermore, although these drugs are apparently toxic (selectivity index < 1), they have synergy with differentiated macrophages of THP-1 cells. But the mechanism of action of these derivatives remains to be determined, although it does not appear to involve efflux pumps inhibited by reserpine and chlorpromazine. On the other hand, sphaerococcenol derivatives do not show activity against Mtb, but against M. smegmatis and against a wide range of Gram-positive bacteria with different degrees of resistance to other antibiotics. Nevertheless, these activities are different, since for the fast-growing nontuberculous Mycobacterium the activity is bactericidal and for the Gram-positive bacteria it is bacteriostatic, which promotes a tolerance phenomenon for these last bacteria. In addition, it has been determined that the efficacy of these derivatives depends on the presence of the hydroxyl group ahead of the plane rather than a carbonyl group. Therefore, although only azaaurone derivatives are promising drugs for the treatment of TB, sphaerococcenol A derivatives are promising drugs for the therapy of infections caused by Grampositive bacteria, thus these two groups of derivatives are important to fight against two threats to global health.
Descrição
Tese de mestrado, Microbiologia Aplicada, 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Atividade Antimicrobiana Derivados de Azauronas Derivados de Sphaerococcenol A Teses de mestrado - 2024