title: The Activity of a Hexameric M17 Metallo-Aminopeptidase Is Associated With Survival ofMycobacterium tuberculosis.
abstract: Mycobacterium tuberculosisis one of the most prevalent human pathogens causing millions of deaths in the last years. Moreover, tuberculosis (TB) treatment has become increasingly challenging owing to the emergence of multidrug resistantM. tuberculosisstrains. Thus, there is an immediate need for the development of new anti-TB drugs. Proteases appear to be a promising approach and may lead to shortened and effective treatments for drug-resistant TB. Although theM. tuberculosisgenome predicts more than 100 genes encoding proteases, only a few of them have been studied. Aminopeptidases constitute a set of proteases that selectively remove amino acids from the N-terminus of proteins and peptides and may act as virulence factors, essential for survival and maintenance of many microbial pathogens. Here, we characterized a leucine aminopeptidase ofM. tuberculosis(MtLAP) as a cytosolic oligomeric metallo-aminopeptidase. Molecular and enzymatic properties lead us to classify MtLAP as a typical member of the peptidase family M17. Furthermore, the aminopeptidase inhibitor bestatin strongly inhibited MtLAP activity,in vitro M. tuberculosisgrowth and macrophage infection. In murine model of TB, bestatin treatment reduced bacterial burden and lesion in the lungs of infected mice. Thus, our data suggest that MtLAP participates in important metabolic pathways ofM. tuberculosisnecessary for its survival and virulence and consequently may be a promising target for new anti-TB drugs.
authors.affiliation: Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia Universidade de BrasíliaBrasília, Brazil; Instituto de Patologia Tropical e Saúde Pública Universidade Federal de GoiásGoiânia, Brazil.
authors.forename: Andre F
authors.initials: AF
authors.lastname: Correa
authors.affiliation: Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia Universidade de Brasília Brasília, Brazil.
authors.forename: Izabela M D
authors.initials: IM
authors.lastname: Bastos
authors.affiliation: Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia Universidade de Brasília Brasília, Brazil.
authors.forename: David
authors.initials: D
authors.lastname: Neves
authors.affiliation: Instituto de Patologia Tropical e Saúde Pública Universidade Federal de Goiás Goiânia, Brazil.
authors.forename: Andre
authors.initials: A
authors.lastname: Kipnis
authors.affiliation: Instituto de Patologia Tropical e Saúde Pública Universidade Federal de Goiás Goiânia, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Junqueira-Kipnis
authors.affiliation: Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia Universidade de Brasília Brasília, Brazil.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: de Santana
keywords: M17 metallo protease; MtLAP; bestatin; leucine aminopeptidase; proteases; tuberculosis