Avaliação da atividade anti-Mycobacterium tuberculosis in vitro e in vivo em modelo alternativo Galleria mellonella de análogos monocetônicos de curcumina
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Data
2021-03-16
Autores
Morandim, Emanuela Americo
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Universidade Estadual Paulista (Unesp)
Resumo
A tuberculose (TB) é a doença infecciosa mais mortal do mundo, de acordo com a Organização Mundial da Saúde (OMS) foram relatados 10 milhões de novos casos mundiais de TB apenas em 2019, dentre eles houve 1,4 milhão de mortes. Atualmente a TB causa mais óbitos do que a Síndrome da Imunodeficiência Adquirida (AIDS) e é estimado que em 2050 as mortes por infecções bacterianas resistentes serão a causa número um. Devido a urgente necessidade na descoberta de novos fármacos para a TB e visto que há milhares de anos as plantas foram a fonte de praticamente todas as preparações medicinais, os produtos naturais empregam um importante papel na descoberta de novos medicamentos. A curcumina que está presente nos rizomas do açafrão e apresenta diversas bioatividades, incluindo a antibacteriana, foi empregada como base para a síntese de sete análogos monocetônicos. O objetivo desse trabalho foi avaliar a atividade destes análogos frente Mycobacterium tuberculosis, o principal agente causador da TB. A concentração inibitória mínima dos análogos foi entre 2,5 µM e 7,9 µM para bacilos sensíveis, o que é uma ótima inibição, e também inibiram de forma eficaz bactérias com perfil de resistência múltipla (MDR-TB) e extensivas (XDR-TB), sugerindo que esses análogos provavelmente apresentam um mecanismo de ação diferenciado. Em ensaios intramacrofágicos, os análogos foram capazes de inibir em até 80% as micobactérias contidas no interior do macrófago. Os análogos apresentam um excelente índice de seletividade com valores que chegam a 64,5 e de modo geral, foram menos tóxicos e mais seletivos para macrófago do que para fibroblastos pulmonares humanos e hepatócitos de carcinoma hepatocelular estudados nos ensaios de citotoxicidade. Os análogos podem ser caracterizados como substâncias de espectro de atividade estreito, por não apresentarem inibição frente a outros patógenos gram-positivos e gram-negativos testados e demonstraram ser compostos seguros em relação à toxicidade in vivo em Galleria mellonella. Com os resultados obtidos, os análogos monocetônicos de curcumina inéditos na literatura, demonstraram que são candidatos promissores a fármacos contra a TB, tanto para bactérias sensíveis quanto para bactérias resistentes, o que é essencial para o desenvolvimento de novas terapias anti-TB atualmente, além da baixa toxicidade encontrada.
Tuberculosis (TB) is the most deadly infectious disease in the world. According to the World Health Organization (WHO) 10 million new TB cases worldwide were reported only in 2019, of which there were 1.4 million deaths. Currently, TB causes more deaths than Acquired Immunodeficiency Syndrome (AIDS) and it is estimated that in 2050 deaths from resistant bacterial infections will be the number one cause. Due to the urgent need to discover new drugs for TB and since plants were used as the source of almost all medicinal preparations for thousands of years, natural products play an important role in the discovery of new drugs. Curcumin is present in the turmeric rhizomes and has several bioactivities, including antibacterial, and it was used as a basis for the synthesis of seven monocarbonyl analogues. The objective of this work was to evaluate the activity of these analogues against Mycobacterium tuberculosis, the main causative agent of TB. The minimum inhibitory concentration of the analogues was between 2.5 µM and 7.9 µM for sensitive bacilli, which is an excellent inhibition, and they also effectively inhibited bacteria with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) profile, suggesting that these analogues probably have differentiated mechanisms of action. In intramacrophagic assays, the analogues were able to inhibit mycobacteria contained in the macrophage by up to 80%. The analogues have an excellent selectivity index with values reaching 64.5 and, in general, they were less toxic and more selective for macrophages than for human pulmonary fibroblasts and hepatocellular carcinoma hepatocytes studied in cytotoxicity assays. The analogues can be characterized as substances of narrow-spectrum activity, as they do not present inhibition against other tested gram-positive and gram-negative pathogens and have shown to be safe compounds, as they do not present toxicity in vivo in relation to the alternative model Galleria mellonella. From the obtained results, the monocarbonyl analogues of curcumin, unprecedented in the literature, demonstrate that they are promising candidates for drugs against TB, both for sensitive and resistant bacteria, which is essential for the development of new anti-TB therapies today, in addition to the low toxicity found.
Tuberculosis (TB) is the most deadly infectious disease in the world. According to the World Health Organization (WHO) 10 million new TB cases worldwide were reported only in 2019, of which there were 1.4 million deaths. Currently, TB causes more deaths than Acquired Immunodeficiency Syndrome (AIDS) and it is estimated that in 2050 deaths from resistant bacterial infections will be the number one cause. Due to the urgent need to discover new drugs for TB and since plants were used as the source of almost all medicinal preparations for thousands of years, natural products play an important role in the discovery of new drugs. Curcumin is present in the turmeric rhizomes and has several bioactivities, including antibacterial, and it was used as a basis for the synthesis of seven monocarbonyl analogues. The objective of this work was to evaluate the activity of these analogues against Mycobacterium tuberculosis, the main causative agent of TB. The minimum inhibitory concentration of the analogues was between 2.5 µM and 7.9 µM for sensitive bacilli, which is an excellent inhibition, and they also effectively inhibited bacteria with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) profile, suggesting that these analogues probably have differentiated mechanisms of action. In intramacrophagic assays, the analogues were able to inhibit mycobacteria contained in the macrophage by up to 80%. The analogues have an excellent selectivity index with values reaching 64.5 and, in general, they were less toxic and more selective for macrophages than for human pulmonary fibroblasts and hepatocellular carcinoma hepatocytes studied in cytotoxicity assays. The analogues can be characterized as substances of narrow-spectrum activity, as they do not present inhibition against other tested gram-positive and gram-negative pathogens and have shown to be safe compounds, as they do not present toxicity in vivo in relation to the alternative model Galleria mellonella. From the obtained results, the monocarbonyl analogues of curcumin, unprecedented in the literature, demonstrate that they are promising candidates for drugs against TB, both for sensitive and resistant bacteria, which is essential for the development of new anti-TB therapies today, in addition to the low toxicity found.
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Palavras-chave
Mycobacterium tuberculosis, curcumina, análogos, atividade antituberculose, Galleria mellonella.