A Ferritin Mutant of Mycobacterium tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable To Establish a Chronic Infection in Mice

Pandey, Ramesh C.; Rodríguez, G. Marcela

doi:10.1128/iai.00229-12

Cited by 98 publications

(118 citation statements)

References 41 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

“…A recent study demonstrated that an M. tuberculosis double deletion mutant of bfrA and bfrB exhibited vulnerability to oxidative stress (14), and the Mtb⌬bfrB mutant has greater susceptibility than the Mtb⌬bfrA mutant (13,14), highlighting the importance of MtBfrB in M. tuberculosis survival during oxidative assault. MtBfrB has antioxidant properties by storing iron, thereby preventing the generation of hydroxyl radicals upon oxygen exposure.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of a Mycobacterium tuberculosis Nanocompartment and Its Potential Cargo Proteins

Contreras¹,

Joens

McMath³

et al. 2014

Journal of Biological Chemistry

119

View full text Add to dashboard Cite

Background: Mycobacterium tuberculosis has a probable nanocompartment (Mt-Enc). Results: Mt-Enc self-assembles into a 60-subunit cage that encapsulates enzymes via their C-terminal tails, which remain active within Mt-Enc. Conclusion: Cargo proteins are potentially involved in host oxidative stress response, suggesting that enzyme encapulation may be a mechanism to evade host immune assault. Significance: Mt-Enc may be utilized as a novel therapeutic delivery mechanism.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Mt-BfrB, one of the two iron storage ferritin proteins within M. tuberculosis, has a C-terminal tail (Fig. 1A) and has displayed antioxidant properties (13,14). In addition, an enzyme involved in folate metabolism, 7,8-dihydroneopterin aldolase (Mt-FolB), also has an aliphatic C-terminal extension (Fig.…”

mentioning

confidence: 99%

Characterization of a Mycobacterium tuberculosis Nanocompartment and Its Potential Cargo Proteins

Contreras¹,

Joens

McMath³

et al. 2014

Journal of Biological Chemistry

119

View full text Add to dashboard Cite

show abstract

“…Studies with the bfrA and bfrB knockout mutants established the importance of the iron storage proteins (38,68,69), particularly BfrB, whose absence resulted in iron toxicity. The bfrB mutants did not survive in experimental mice, showing that BrfB was essential for the virulence of M. tuberculosis.…”

Section: Toxicity Of Iron: Protective Role Of the Iron Storage Proteimentioning

confidence: 99%

Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

2016

View full text Add to dashboard Cite

Mycobacterium tuberculosis requires iron for normal growth but faces a limitation of the metal ion due to its low solubility at biological pH and the withholding of iron by the mammalian host. The pathogen expresses the Fe 3؉ -specific siderophores mycobactin and carboxymycobactin to chelate the metal ion from insoluble iron and the host proteins transferrin, lactoferrin, and ferritin. Siderophore-mediated iron uptake is essential for the survival of M. tuberculosis, as knockout mutants, which were defective in siderophore synthesis or uptake, failed to survive in low-iron medium and inside macrophages. But as excess iron is toxic due to its catalytic role in the generation of free radicals, regulation of iron uptake is necessary to maintain optimal levels of intracellular iron. The focus of this review is to present a comprehensive overview of iron homeostasis in M. tuberculosis that is discussed in the context of mycobactin biosynthesis, transport of iron across the mycobacterial cell envelope, and storage of excess iron. The clinical significance of the serum iron status and the expression of the iron-regulated protein HupB in tuberculosis (TB) patients is presented here, highlighting the potential of HupB as a marker, notably in extrapulmonary TB cases.

show abstract

“…Especificamente, o análogo nucleosídeo (34) demonstrou CIM 99 de 0,29 μmol L -1 , similar a isoniazida (0.18 μmol L -1 ) (Figura 12). 91 Entretanto, apesar das características farmacodinâmicas promissoras, a molécula demonstrou características farmacocinéticas inadequadas, como baixa biodisponibilidade e tempo de meia vida reduzido (t 1/2 = 11 min).…”

Section: Alvos Envolvidos Com O Metabolismo Do Ferrounclassified

“…91 Entretanto, apesar das características farmacodinâmicas promissoras, a molécula demonstrou características farmacocinéticas inadequadas, como baixa biodisponibilidade e tempo de meia vida reduzido (t 1/2 = 11 min). 94 Estudos adicionais descreveram um inibidor (35) (Figura 12) da enzima MbtA com CIM 99 de 0,78 μmol L -1 contra cepas de MTB H 37 Rv e melhores propriedades farmacocinéticas (t 1/2 = 62 min) que o seu análogo (34). 95 Outro alvo envolvido na captura de ferro é o EccB3, o qual é um componente do sistema de secreção ESX-3 tipo VII.…”

Section: Alvos Envolvidos Com O Metabolismo Do Ferrounclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

View full text Add to dashboard Cite

POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

show abstract

A Ferritin Mutant of Mycobacterium tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable To Establish a Chronic Infection in Mice

Abstract: ABSTRACTIron is an essential, elusive, and potentially toxic nutrient for most pathogens, includingMycobacterium tuberculosis. Due to the poor solubility of ferric iron under aerobic conditions, free iron is not found in the host.M. tube… Show more

Cited by 98 publications

References 41 publications

Characterization of a Mycobacterium tuberculosis Nanocompartment and Its Potential Cargo Proteins

Characterization of a Mycobacterium tuberculosis Nanocompartment and Its Potential Cargo Proteins

Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Contact Info

Product

Resources

About