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MmpL3 membrane transporter as a potential therapeutic target in the development of tuberculosis treatment drugs
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A tuberculose (TB) é a segunda maior causa de morte por infeção no mundo, com cerca de 1/3 da população infetada pelo agente causador, Mycobacterium tuberculosis (Mtb). A forma mais prevalente de TB é a tuberculose pulmonar, que é extremamente contagiosa e pode ser letal se não for tratada.
O surgimento de estirpes multirresistentes (MDR) e extensivamente resistentes (XDR) é uma das barreiras mais significativas para a erradicação da doença, contribuindo significativamente para a desistência pelos pacientes devido à longa duração do tratamento e efeitos colaterais de difícil manejo. Portanto, fármacos anti-tuberculares
com modos de ação inovadores de alta potência e mínima toxicidade são urgentemente necessários.
O envelope da célula Mtb, que é composto por três camadas: peptidoglicano, arabinogalactano e ácidos micólicos, é essencial para a proliferação celular, virulência e resistência a antibióticos.
A arquitetura única da membrana celular micobacteriana é significativa na patogénese do Mtb. O patógenio depende de sua parede celular para o crescimento e sobrevivência. É rico em lipídios e extremamente impermeável, permitindo que a micobactéria se multiplique dentro dos macrófagos e permaneça por longos períodos
de tempo no hospedeiro infetado.
A proteína de membrana micobacteriana grande 3 (MmpL3) é um transportador de membrana interna de Mtb que exporta monomicolatos de trealose (TMMs), um precursor do componente da membrana externa, dimicolato de trealose (TDM), bem como dos ácidos micólicos ligados ao arabinogalactano, que juntos constituem a
micomembrana.
Quando o transportador MmpL3 é inibido, o TMM acumula-se intracelularmente e os níveis do complexo peptidoglicano micolilarabinogalactano (mAGP) e TDM diminuem, resultando em enfraquecimento e morte celular. Portanto, a MmpL3 é um alvo atraente e promíscuo para fármacos anti-tuberculares e desempenha um papel
importante na biossíntese do envelope celular.
Usando abordagens genómicas e proteómicas, novos alvos de fármacos anti tuberculosos foram identificados. Entre os fármacos que inibem MmpL3 estão derivados de etilenodiamina, derivados de amida (por exemplo, indol-2 carboxamidas, benzotiazol amidas, THPPs), pirróis, pirazoles, adamantil ureias, benzimidazóis e espiros.
Atualmente, não há fármacos aprovado pela FDA para terapia de tuberculose que tenha como alvo a proteína MmpL3.
Tuberculosis (TB) is the second biggest cause of death from infection worldwide, with an estimated 1/3 of the population infected with the causative agent, Mycobacterium tuberculosis (Mtb). The most prevalent form of TB is pulmonary tuberculosis, which is extremely contagious and may be lethal if left untreated. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains is one of the most significant barriers to the disease's eradication, contributing significantly to patient dropout due to the lengthy duration of treatment and difficult to-manage side effects. Therefore, antituberculosis drugs with innovative modes of action, high potency, chemical stability, and minimal toxicity are urgently needed. The Mtb cell envelope, which is made up of three layers: peptidoglycan, arabinogalactan, and mycolic acids, is essential for cell proliferation, virulence, and antibiotic resistance. The unique architecture of the mycobacterial cell membrane is significant in the pathogenesis of Mtb. The pathogen relies on its cell wall for growth and survival. It is lipid-rich and extremely impermeable, allowing the virus to multiply within macrophages and remain for long periods of time in the infected host. Mycobacterial membrane protein large (MmpL3) is Mtb inner membrane transporter that exports trehalose monomycolates (TMMs), a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids linked to arabinogalactan, which together constitute the mycomembrane. When the MmpL3 transporter is inhibited, TMM accumulates intracellularly and mycolyl arabinogalactan peptidoglycan (mAGP) and TDM levels decrease, resulting in cell weakening and death. Hence MmpL3 is an attractive and promiscuous target for TB drugs that plays an important role in cell envelope biosynthesis. Using genomic and proteomic approaches, new antituberculosis drug targets have been identified. Among the scaffolds that inhibit MmpL3 are ethylenediamine derivatives, carboxamide derivatives (e.g., indole-2 carboxamides, benzothiazole amides, THPPs), pyrroles, pyrazoles, adamantyl ureas, benzimidazoles, and spirocycles. There is currently no FDA-approved drug for tuberculosis therapy that targets the MmpL3 protein.
Tuberculosis (TB) is the second biggest cause of death from infection worldwide, with an estimated 1/3 of the population infected with the causative agent, Mycobacterium tuberculosis (Mtb). The most prevalent form of TB is pulmonary tuberculosis, which is extremely contagious and may be lethal if left untreated. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains is one of the most significant barriers to the disease's eradication, contributing significantly to patient dropout due to the lengthy duration of treatment and difficult to-manage side effects. Therefore, antituberculosis drugs with innovative modes of action, high potency, chemical stability, and minimal toxicity are urgently needed. The Mtb cell envelope, which is made up of three layers: peptidoglycan, arabinogalactan, and mycolic acids, is essential for cell proliferation, virulence, and antibiotic resistance. The unique architecture of the mycobacterial cell membrane is significant in the pathogenesis of Mtb. The pathogen relies on its cell wall for growth and survival. It is lipid-rich and extremely impermeable, allowing the virus to multiply within macrophages and remain for long periods of time in the infected host. Mycobacterial membrane protein large (MmpL3) is Mtb inner membrane transporter that exports trehalose monomycolates (TMMs), a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids linked to arabinogalactan, which together constitute the mycomembrane. When the MmpL3 transporter is inhibited, TMM accumulates intracellularly and mycolyl arabinogalactan peptidoglycan (mAGP) and TDM levels decrease, resulting in cell weakening and death. Hence MmpL3 is an attractive and promiscuous target for TB drugs that plays an important role in cell envelope biosynthesis. Using genomic and proteomic approaches, new antituberculosis drug targets have been identified. Among the scaffolds that inhibit MmpL3 are ethylenediamine derivatives, carboxamide derivatives (e.g., indole-2 carboxamides, benzothiazole amides, THPPs), pyrroles, pyrazoles, adamantyl ureas, benzimidazoles, and spirocycles. There is currently no FDA-approved drug for tuberculosis therapy that targets the MmpL3 protein.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2022, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Mycobacterium tuberculosis MmpL3 transporte Small molecule inhibitors Cell-wall biogenesis Drug-resistant tuberculosis Mestrado integrado - 2022