Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

The ongoing impacts of hepatitis C - a systematic narrative review of the literature

Extent: 13p.BackgroundMany countries have developed, or are developing, national strategies aimed at reducing the harms associated with hepatitis C infection. Making these strategies relevant to the vast majority of those affected by hepatitis C requires a more complete understanding of the short and longer term impacts of infection. We used a systematic approach to scope the literature to determine what is currently known about the health and psychosocial impacts of hepatitis C along the trajectory from exposure to ongoing chronic infection, and to identify what knowledge gaps remain.MethodsPubMed, Current Contents and PsychINFO databases were searched for primary studies published in the ten years from 2000-2009 inclusive. Two searches were conducted for studies on hepatitis C in adult persons focusing on: outcomes over time (primarily cohort and other prospective designs); and the personal and psychosocial impacts of chronic infection. All retrieved studies were assessed for eligibility according to specific inclusion/exclusion criteria, data completeness and methodological coherence. Outcomes reported in 264 included studies were summarized, tabulated and synthesized.ResultsInjecting drug use (IDU) was a major risk for transmission with seroconversion occurring relatively early in injecting careers. Persistent hepatitis C viraemia, increasing age and excessive alcohol consumption independently predicted disease progression. While interferon based therapies reduced quality of life during treatment, improvements on baseline quality of life was achieved post treatment--particularly when sustained viral response was achieved. Much of the negative social impact of chronic infection was due to the association of infection with IDU and inflated assessments of transmission risks. Perceived discrimination was commonly reported in health care settings, potentially impeding health care access. Perceptions of stigma and experiences of discrimination also had direct negative impacts on wellbeing and social functioning.ConclusionsHepatitis C and its management continue to have profound and ongoing impacts on health and social well being. Biomedical studies provided prospective information on clinical aspects of infection, while the broader social and psychological studies presented comprehensive information on seminal experiences (such as diagnosis and disclosure). Increasing the focus on combined methodological approaches could enhance understanding about the health and social impacts of hepatitis C along the life course.Emma R Miller, Stephen McNally, Jack Wallace, Marisa Schlichthors