Drug resistance mechanisms and novel drug targets for tuberculosis therapy

Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.     

Prioritizing genomic drug targets in pathogens: application to Mycobacterium tuberculosis

We have developed a software program that weights and integrates specific properties on the genes in a pathogen so that they may be ranked as drug targets. We applied this software to produce three prioritized drug target lists for Mycobacterium tuberculosis, the causative agent of tuberculosis, a disease for which a new drug is desperately needed. Each list is based on an individual criterion. The first list prioritizes metabolic drug targets by the uniqueness of their roles in the M. tuberculosis metabolome ("metabolic chokepoints") and their similarity to known "druggable" protein classes (i.e., classes whose activity has previously been shown to be modulated by binding a small molecule). The second list prioritizes targets that would specifically impair M. tuberculosis, by weighting heavily those that are closely conserved within the Actinobacteria class but lack close homology to the host and gut flora. M. tuberculosis can survive asymptomatically in its host for many years by adapting to a dormant state referred to as "persistence." The final list aims to prioritize potential targets involved in maintaining persistence in M. tuberculosis. The rankings of current, candidate, and proposed drug targets are highlighted with respect to these lists. Some features were found to be more accurate than others in prioritizing studied targets. It can also be shown that targets can be prioritized by using evolutionary programming to optimize the weights of each desired property. We demonstrate this approach in prioritizing persistence targets.     

From cancer metabolism to new biomarkers and drug targets

Great interest is presently given to the analysis of metabolic changes that take place specifically in cancer cells. In this review we summarize the alterations in glycolysis, glutamine utilization, fatty acid synthesis and mitochondrial function that have been reported to occur in cancer cells and in human tumors. We then propose considering cancer as a system-level disease and argue how two hallmarks of cancer, enhanced cell proliferation and evasion from apoptosis, may be evaluated as system-level properties, and how this perspective is going to modify drug discovery. Given the relevance of the analysis of metabolism both for studies on the molecular basis of cancer cell phenotype and for clinical applications, the more relevant technologies for this purpose, from metabolome and metabolic flux analysis in cells by Nuclear Magnetic Resonance and Mass Spectrometry technologies to positron emission tomography on patients, are analyzed. The perspectives offered by specific changes in metabolism for a new drug discovery strategy for cancer are discussed and a survey of the industrial activity already going on in the field is reported.     

Antimalarial drug development and new targets

The Molecular Approaches to Malaria (MAM2000) conference, Lorne, Australia, 2-5 February 2000, brought together world-class malaria research scientists. The development of new tools and technologies - transfection, DNA microarrays and proteomic analysis - and the availability of DNA sequences generated by the Malaria Genome Project, along with more classic approaches, have facilitated the identification of novel drug targets, the development of new antimalarials and the generation of a deeper understanding of the molecular mechanism(s) of drug resistance in malaria. It is hoped that combinations of these technologies could lead to strategies that enable the development of effective, efficient and affordable new drugs to overcome drug-resistant malaria, as discussed at MAM2000 and outlined here by Ian Macreadie and colleagues.     

Identifying new targets in leukemogenesis using computational approaches

There is a need to identify novel targets in Acute Lymphoblastic Leukemia (ALL), a hematopoietic cancer affecting children, to improve our understanding of disease biology and that can be used for developing new therapeutics. Hence, the aim of our study was to find new genes as targets using in silico studies; for this we retrieved the top 10% overexpressed genes from Oncomine public domain microarray expression database; 530 overexpressed genes were short-listed from Oncomine database. Then, using prioritization tools such as ENDEAVOUR, DIR and TOPPGene online tools, we found fifty-four genes common to the three prioritization tools which formed our candidate leukemogenic genes for this study. As per the protocol we selected thirty training genes from PubMed. The prioritized and training genes were then used to construct STRING functional association network, which was further analyzed using cytoHubba hub analysis tool to investigate new genes which could form drug targets in leukemia. Analysis of the STRING protein network built from these prioritized and training genes led to identification of two hub genes, SMAD2 and CDK9, which were not implicated in leukemogenesis earlier. Filtering out from several hundred genes in the network we also found MEN1, HDAC1 and LCK genes, which re-emphasized the important role of these genes in leukemogenesis. This is the first report on these five additional signature genes in leukemogenesis. We propose these as new targets for developing novel therapeutics and also as biomarkers in leukemogenesis, which could be important for prognosis and diagnosis.     

Synaptic plasticity and neuropathology: new approaches in drug discovery

Neuronal plasticity is now known to be very important in the adult, both in the formation of new synaptic connections and of new neurones (neurogenesis) and of glial cells. However, old age and stress can inhibit this plasticity and lead to cerebral atrophy. The time course of changes in neuronal plasticity involves, in the first milliseconds to seconds, changes in synaptic strength (long term potentialisation, LTP, or long term depression, LTD), then, over minutes to hours, changes in the number of synaptic connections (linked to changes in neurotrophic factors), and over weeks to months, to changes in neuronal reconfiguration. These changes in brain systems are particularly targeted in psychiatric disorders to the areas which are sensitive to stress and play roles in memory and emotion (hippocampus, amygdala and prefrontal cortex). The discovery and development of drugs modifying neuronal plasticity and neurotrophins production has been a priority for Servier research for the last ten years; Servier has a clinically effective antidepressant, tianeptine (Stablon), with a favourable side effect profile, but which does not inhibit the uptake of serotonin, or other monoamines. However, this drug can reverse the deleterious effects of stress on neuronal plasticity, thereby acting on the causes of psychiatric disorders. Furthermore, a new research area is being investigated - facilitation of AMPA receptors, favouring the production of neurotrophic factors.     

Blood-brain barrier and new approaches to brain drug delivery.

Morbidity caused by brain dysfunction affects more than 50 million persons in the United States. Although new neuropharmaceuticals have the potential for treating specific brain diseases, they may not effectively enter brain from blood. Safe strategies are needed for drug delivery through the brain capillary wall, which makes up the blood-brain barrier in vivo. Two of these strategies are reviewed, as are related new developments in the molecular and cell biology of the brain capillary endothelium. The production of chimeric peptides represents a physiologic-based strategy for drug delivery. It entails the covalent coupling of the neuropharmaceutical to a brain transport vector, allowing transportation through the blood-brain barrier. Another strategy is biochemical opening of the blood-brain barrier: intracarotid leukotriene infusion is a method for selectively increasing blood-brain barrier permeability in brain tumors without affecting barrier permeability in normal brain tissue.     

Monogenic hypercholesterolemias: New genes,new drug targets

This review is focused on recent data on structure and functions of PCSK9 proprotein convertase, a newly identified participant in cholesterol metabolism in mammalian organisms, including humans. Proprotein convertase acts as a molecular chaperone for the low density lipoprotein (LDL) receptor, targeting it to the lysosomal degradation pathway. Various mutations increasing the PCSK9 affinity toward the LDL receptor cause autosomal dominant hypercholesterolemia. In contrast, loss-of-function mutations in PCSK9 gene decrease the blood plasma cholesterol level, thus acting as a protection factor against atherosclerosis and coronary heart disease. It is supposed that pharmacological agents inhibiting the interaction between PCSK9 and LDL receptor may substantially amplify the benefits of drugs—statins and cholesterol absorption blockers—in the treatment of all types of hypercholesterolemia, including its widespread multigenic and multifactorial forms.     

Genomics and the discovery of new drug targets

Molecular medicine and genomics technologies are inseparable for defining new molecular targets. cDNA databases and elementary informatic tools provide instantaneous glimpses of gene families or tissue-restricted expression patterns as a means of new target identification. In addition, cDNA microarrays and two-dimensional gel electrophoresis unmask the expression of genes with unassigned or unexpected functions. Depletion of mRNA with ribozymes or neutralization of proteins with intracellular antibodies enable investigators to reject or embrace new molecular hypotheses about the determinants of disease, pharmacology or toxicology.     

150 years beyond Darwin's Origin of species: finding new approaches to reconstruct early animal phylogeny

The conference ‘Celebrating Darwin: From the Origin of Species to Deep Metazoan Phylogeny’ was held at the Humboldt University in Berlin, from 3 to 6 March 2009. Specialists from the fields of bioinformatics, molecular biology, developmental biology, comparative morphology and paleontology joined forces to present and discuss novel approaches in reconstructing the still unresolved early branching patterns of the metazoan tree of life.     

Metabolomics: Creating new potentials for unraveling the mechanisms in response to salt and drought stress and for the biotechnological improvement of xero-halophytes

Breeders have long been interested in understanding the biological function and mechanism of xero-halophytes and their ability for growth in drought-stricken and salinized environments. However, the mechanisms in response to stress have been difficult to unravel because their defenses require regulatory changes to the activation of multiple genes and pathways. Metabolomics is becoming a key tool in comprehensively understanding the cellular response to abiotic stress and represents an important addition to the tools currently employed in genomics-assisted selection for plant improvement. In this review, we highlight the applications of plant metabolomics in characterizing metabolic responses to salt and drought stress, and identifying metabolic quantitative trait loci (QTLs). We also discuss the potential of metabolomics as a tool to unravel stress response mechanisms, and as a viable option for the biotechnological improvement of xero-halophytes when no other genetic information such as linkage maps and QTLs are available, by combining with germplasm-regression-combined marker-trait association identification.     

Antifungal drug development: the identification of new targets.

With the increasing prevalence of life-threatening systemic fungal infections in the human population, there is a need to develop new, more-effective antifungal agents. This, in turn, will depend upon the identification and exploitation of new antifungal targets--aspects of fungal cytology, metabolism and gene expression which are important for fungal pathogenesis, but which have no mammalian host counterpart. Such new targets have been identified through a combination of classical genetic, cytological and biochemical studies and are reviewed here, as is the potential for applying recombinant DNA techniques as a means of confirming the role of the identified gene products in pathogenesis.     

The discovery and validation of new drug targets in cancer

Advances in our understanding of the signal transduction pathways involved in cellular growth control have provided several new strategies for cancer therapy. Recent advances now make it possible to develop selective inhibitors targeting genomic instability, the growth, survival, and invasion of the tumor, and its nourishment through the growth of new blood vessels.     

Metabolomics: creating new potentials for unraveling the mechanisms in response to salt and drought stress and for the biotechnological improvement of xero-halophytes

Breeders have long been interested in understanding the biological function and mechanism of xero-halophytes and their ability for growth in drought-stricken and salinized environments. However, the mechanisms in response to stress have been difficult to unravel because their defenses require regulatory changes to the activation of multiple genes and pathways. Metabolomics is becoming a key tool in comprehensively understanding the cellular response to abiotic stress and represents an important addition to the tools currently employed in genomics-assisted selection for plant improvement. In this review, we highlight the applications of plant metabolomics in characterizing metabolic responses to salt and drought stress, and identifying metabolic quantitative trait loci (QTLs). We also discuss the potential of metabolomics as a tool to unravel stress response mechanisms, and as a viable option for the biotechnological improvement of xero-halophytes when no other genetic information such as linkage maps and QTLs are available, by combining with germplasm-regression-combined marker-trait association identification.     

Latent tuberculosis: interaction of virulence factors in Mycobacterium tuberculosis

Molecular Biology Reports - Tuberculosis (TB) remains a prominent health concern worldwide. Besides extensive research and vaccinations available, attempts to control the pandemic are cumbersome...     

Old drugs, new tricks: using genetically sensitized yeast to reveal drug targets

A study in this issue of Cell illustrates the power of applying genomic approaches with model systems to characterize the biological activity of small molecules and to identify their cellular targets, which can clarify the mode of action of human therapeutics.     

Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery

Classic Parkinson's disease (PD) is characterized by fibrillar alpha-synuclein inclusions known as Lewy bodies in the substantia nigra, which are associated with nigrostriatal degeneration. However, alpha-synuclein pathologies accumulate throughout the CNS in areas that also undergo progressive neurodegeneration, leading to dementia and other behavioral impairments in addition to parkinsonism. Although mutations in the alpha-synuclein gene only cause Lewy body PD in rare families, and although there are multiple other, albeit rare, genetic causes of familial parkinsonism, sporadic Lewy body PD is the most common movement disorder, and insights into mechanisms underlying alpha-synuclein-mediated neurodegeneration provide novel targets for the discovery of disease-modifying therapies for PD and related neurodegenerative alpha-synucleinopathies.