RESUMO
Mycobacterium abscessus is an opportunistic pathogen that mainly colonizes and infects cystic fibrosis patients' lungs. M. abscessus is naturally resistant to many antibiotics such as rifamycin, tetracyclines and ß-lactams. The current therapeutic regimens are not very effective and are mostly based on repurposed drugs used against Mycobacterium tuberculosis infections. Thus, new approaches and novel strategies are urgently needed. This review aims to provide an overview of the latest ongoing findings to fight M. abscessus infections by analyzing emerging and alternative treatments, novel drug delivery strategies, and innovative molecules.
Assuntos
Fibrose Cística , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Humanos , Fibrose Cística/tratamento farmacológico , Antibacterianos/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , beta-Lactamas/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 µM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirrolidinas/química , Pirrolidinas/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/metabolismo , Oxirredutases/química , Oxirredutases/metabolismo , Conformação Proteica , Pirrolidinas/metabolismo , Pirrolidinonas/metabolismo , Relação Estrutura-AtividadeRESUMO
To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target.
Assuntos
Antituberculosos/farmacologia , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/metabolismo , Tiofenos/farmacologia , Ativação Metabólica , Animais , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Carbono-Nitrogênio Ligases/química , Carbono-Nitrogênio Ligases/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Células Hep G2 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Oxirredutases/química , Conformação Proteica , Tiofenos/químicaRESUMO
The re-emergence of tuberculosis in recent years led the World Health Organization (WHO) to launch the Stop TB Strategy program. Beside repurposing the existing drugs and exploring novel molecular combinations, an essential step to face the burden of tuberculosis will be to develop new drugs by identifying vulnerable bacterial targets. Recent studies have focused on decaprenylphosphoryl-D-ribose oxidase (DprE1) of Mycobacterium tuberculosis, an essential enzyme involved in cell wall metabolism, for which new promising molecules have proved efficacy as antitubercular agents. This review summarizes the state of the art concerning DprE1 in terms of structure, enzymatic activity and inhibitors. This enzyme is emerging as one of the most vulnerable target in M. tuberculosis.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Oxirredutases/antagonistas & inibidores , Tuberculose/tratamento farmacológico , Oxirredutases do Álcool , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Parede Celular/efeitos dos fármacos , Parede Celular/genética , Parede Celular/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Oxirredutases/química , Oxirredutases/genética , Oxirredutases/metabolismo , Tuberculose/microbiologiaRESUMO
New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.
Assuntos
Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Polissacarídeos/biossíntese , Racemases e Epimerases/antagonistas & inibidores , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Tiazinas/farmacologia , Tiazinas/uso terapêutico , Tuberculose/tratamento farmacológico , Sequência de Aminoácidos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Arabinose/metabolismo , Parede Celular/metabolismo , Farmacorresistência Bacteriana , Inibidores Enzimáticos/líquido cefalorraquidiano , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Etambutol/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genes Bacterianos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Mycobacterium/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Racemases e Epimerases/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Tiazinas/síntese química , Tiazinas/química , Tuberculose/microbiologiaRESUMO
Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. Moreover, the recent isolation of M. tuberculosis strains resistant to both first- and second-line antitubercular drugs (XDR-TB) threatens to make the treatment of this disease extremely difficult and becoming a threat to public health worldwide. Recently, it has been shown that azoles are potent inhibitors of mycobacterial cell growth and have antitubercular activity in mice, thus favoring the hypothesis that these drugs may constitute a novel strategy against tuberculosis disease. To investigate the mechanisms of resistance to azoles in mycobacteria, we isolated and characterized several spontaneous azoles resistant mutants from M. tuberculosis and Mycobacterium bovis BCG. All the analyzed resistant mutants exhibited both increased econazole efflux and increased transcription of mmpS5-mmpL5 genes, encoding a hypothetical efflux system belonging to the resistance-nodulation-division (RND) family of transporters. We found that the up-regulation of mmpS5-mmpL5 genes was linked to mutations either in the Rv0678 gene, hypothesized to be involved in the transcriptional regulation of this efflux system, or in its putative promoter/operator region.