21 research outputs found
The phosphatidyl-myo-inositol mannosyltransferase PimA is essential for Mycobacterium tuberculosis growth in vitro and in vivo.
The cell envelope of Mycobacterium tuberculosis contains glycans and lipids of peculiar structure that play prominent roles in the biology and pathogenesis of tuberculosis. Consequently, the chemical structure and biosynthesis of the cell wall have been intensively investigated in order to identify novel drug targets. Here, we validate that the function of phosphatidyl-myo-inositol mannosyltransferase PimA is vital for M. tuberculosis in vitro and in vivo. PimA initiates the biosynthesis of phosphatidyl-myoinositol mannosides by transferring a mannosyl residue from GDP-Man to phosphatidyl-myo-inositol on the cytoplasmic side of the plasma membrane. To prove the essential nature of pimA in M. tuberculosis, we constructed a pimA conditional mutant by using the TetR-Pip off system and showed that downregulation of PimA expression causes bactericidality in batch cultures. Consistent with the biochemical reaction catalyzed by PimA, this phenotype was associated with markedly reduced levels of phosphatidyl-myo-inositol dimannosides, essential structural components of the mycobacterial cell envelope. In addition, the requirement of PimA for viability was clearly demonstrated during macrophage infection and in two different mouse models of infection, where a dramatic decrease in viable counts was observed upon silencing of the gene. Notably, depletion of PimA resulted in complete clearance of the mouse lungs during both the acute and chronic phases of infection. Altogether, the experimental data highlight the importance of the phosphatidyl-myo-inositol mannoside biosynthetic pathway for M. tuberculosis and confirm that PimA is a novel target for future drug discovery programs
Maxwell A: F1000Prime Recommendation of Evaluation [Neres J et al., ACS Chem Biol 2014]. In F1000Prime, 09 Jan 2015; DOI: 10.3410/f.725248139.793502885. F1000Prime.com/725248139#eval793502885
Tuberculosis (TB) is still a serious problem worldwide, particularly with the advent of drug-resistant strains. Using phenotypic screening, the authors have discovered quinoxaline compounds (especially Ty38c) that are active against extracellular and intracellular Mycobacterium tuberculosis, targeting DprE1, an enzyme involved in cell wall synthesis. The structural work reported in this paper will underpin further efforts to find other compounds that inhibit this target.
There is no doubt that TB is a scourge of humankind, killing >1 million people each year. Current therapy is problematic owing to resistance issues and the long times over which drugs have to be taken. Current work has tended to move away from target-based screening to phenotypic screening. Using this approach, the authors have discovered the quinoxaline compound Ty38c as a TB drug candidate. Initial mutations were found in rv3405c, a transcriptional regulator that controls expression of rv3406, whose gene product inactivates Ty38c. Using an rv3406-deficient strain, the authors show that the actual target of Ty38c is DprE1, which is a known target for other TB inhibitors. Using a range of Ty38c analogues, the authors perform a series of structure-activity experiments, and using X-ray crystallography they reveal the molecular details of the Ty38c-DprE1 interactions.
Taken together, the work represents a tour de force in TB drug discovery research and provides significant hope that new TB agents can be developed from such approaches
Towards better diagnostic criteria for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome
Abstract
Aim: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most common cause of a periodic fever in childhood. The exact pathogenesis and the aetiology of PFAPA are still unknown.
Methods: We conducted a nonâsystematic review of published articles about PFAPA syndrome and summarised the evidence for diagnostic criteria and treatment options for PFAPA.
Results: The first proposed diagnostic criteria for PFAPA, in addition to periodic fever, included aphthous stomatitis, pharyngitis or cervical lymphadenitis in children younger than five years at the beginning of the symptoms. Câreactive protein (CRP) levels and leucocyte counts increase in most patients during episodes. Recent research reveals that tonsillectomy provides an immediate and longâlasting cure for PFAPA, even in the absence of classic criteria of aphthous stomatitis, pharyngitis or cervical adenitis and in children older than five years.
Conclusion: We suggest that PFAPA can be diagnosed in children with at least five regularly occurring fever episodes without any other explanation, even in the absence of aphthous stomatitis, pharyngitis or cervical lymphadenitis and also in children older than five years