Approaches to target identification and validation for tuberculosis drug discovery: a UCT perspective

Warner, Digby F.; Mizrahi, Valerie

doi:10.7196/samj.5437

Cited by 5 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As noted above, investigations of metabolic capacity in M. tuberculosis have been framed largely within the context of drug discovery, with a particular focus on the identification of vital (essential) genes or pathways as potential targets. The "essential gene lists" derived in the landmark studies of Christopher Sassetti, Eric Rubin, and colleagues Sas-setti and Rubin 2003), refined in a series of subsequent iterations exploring different infection models (Rengarajan et al 2005;Brodin et al 2010;Griffin et al 2011;Zhang et al 2013b), have been routinely applied as a starting criterion in target selection and prioritization (Warner and Mizrahi 2012). In turn, this has motivated efforts to develop in vitro growth models that more closely resemble the host environments encountered by M. tuberculosis (Franzblau et al 2012;Dartois and Barry 2013).…”

Section: Tb Drug Discovery and M Tuberculosis Metabolism Targeting Mmentioning

confidence: 99%

Mycobacterium tuberculosis Metabolism

2019

View full text Add to dashboard Cite

Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances-in particular, the development of systems biology tools such as metabolomics-have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host -pathogen interaction through modulation of metabolic functions.Ultimately, the process of pathogenicity itself will be describable in terms of the chemistry of the mycobacterial cell. Cite this article as Cold Spring Harb Perspect Med 2015;5:a021121 www.perspectivesinmedicine.org BOX 1. RECOMMENDED RESOURCES Physiology of Mycobacterium tuberculosis † Cook GM, Berney M, Gebhard S, Heinemann M, Cox RA, Danilchanka O, Niederweis M. 2009. Physiology of mycobacteria. Adv Microb Physiol 55: 81-319. † Russell DG. 2013. The evolutionary pressures that have molded Mycobacterium tuberculosis into an infectious adjuvant. Curr Opin Microbiol 16: 78-84. Central Carbon Metabolism † Ehrt S, Rhee K. 2013. Mycobacterium tuberculosis metabolism and host interaction: Mysteries and paradoxes.

show abstract

Section: Tb Drug Discovery and M Tuberculosis Metabolism Targeting Mmentioning

confidence: 99%

Mycobacterium tuberculosis Metabolism

2019

View full text Add to dashboard Cite

show abstract

“…The "essential gene lists" derived in the landmark studies of Christopher Sassetti, Eric Rubin, and colleagues , refined in a series of subsequent iterations exploring different infection models (Rengarajan et al 2005;Brodin et al 2010;Griffin et al 2011;Zhang et al 2013b), have been routinely applied as a starting criterion in target selection and prioritization (Warner and Mizrahi 2012). In turn, this has motivated efforts to develop in vitro growth models that more closely resemble the host environments encountered by M. tuberculosis (Franzblau et al 2012;Dartois and Barry 2013).…”

Section: Tb Drug Discovery and M Tuberculosis Metabolism Targeting Mmentioning

confidence: 99%

Mycobacterium tuberculosis Metabolism

Warner¹

2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances-in particular, the development of systems biology tools such as metabolomics-have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host -pathogen interaction through modulation of metabolic functions.Ultimately, the process of pathogenicity itself will be describable in terms of the chemistry of the mycobacterial cell.-Wheeler and Ratledge (1994) T he term "metabolism" has a very wide purview. For bacteria, it is commonly used to describe the full set of complex and interconnected chemical transformations that enable individual cells to survive and replicate. In turn, these might be broadly divided into the anabolic pathways that consume energy in generating biomass and the energy-releasing catabolic reactions that channel organic building blocks into diverse cellular structures and pathways. Metabolism also includes pathways that are essential to the ability of bacteria to respond to dynamic environments and to maintain structural integrity in the face of fluctuating nutrient availability. Therefore, in an obligate pathogen such as Mycobacterium tuberculosis whose entire life cycle is driven in the context of human infection, metabolism necessarily underpins both physiology and pathogenesis (Rhee 2013).Owing to this dual role, the metabolism of M. tuberculosis has been the subject of intense research Beste and McFadden 2010). However, although experimental mycobacteriology-in particular, the use of genetic tools to disrupt enzymatic and regulatory functions-has provided critical insights into the metabolic pathways that are esEditors:

show abstract

“…This has led an alarming concern to all researchers to significantly identify the potential virulence factors as a most promising and alternative candidate drug targets that can overwhelm the worse situations of multi-drug resistant bacteria that has a concerning issue of public health sectors [1]. The drastic increase in the bacterial genome projects has paved a path for the identification of potentially novel virulence-associated factors and their possibility as a novel drug target [2]. However, we have many significant sequence databases holds genome and protein sequences resulting in huge amount of data we are unfortunate to have the virulence factors that determine the pathogenesis of the bacteria.…”

Section: Introductionmentioning

confidence: 99%

Enterobacteria virulence factor prediction server

karasu¹,

Dinakaran²,

Sathishkumar³

et al. 2017

IJET

View full text Add to dashboard Cite

The continuous usage of antibiotics has resulted in the increase of multidrug resistance in the bacteria. The drastic increase in the bacterial genome projects has paved a path for the identification of potentially novel virulence-associated factors and their possibility as novel drug targets. Thus in the present study, we have implemented SMO classifiers for the better prediction of proteins based on individual protein sequences amino acid composition (AAC) and the performance of evaluation was checked via threshold dependent parameters such as Sensitivity, Specificity, Accuracy, and Mathew correlation coefficient. The predictions are based on the dataset incorporated in the database of five major virulence factors from six pathogens of Enterobacteriacae.This comprehensive database can serve as a source for the selection of significant virulence factor based on the intellectual Gene ontology terms that play a critical role in the pathogenesis and its surveillance in the host.

show abstract

Approaches to target identification and validation for tuberculosis drug discovery: a UCT perspective

Cited by 5 publications

References 15 publications

Mycobacterium tuberculosis Metabolism

Mycobacterium tuberculosis Metabolism

Mycobacterium tuberculosis Metabolism

Enterobacteria virulence factor prediction server

Contact Info

Product

Resources

About