Drug discovery today. Disease mechanisms最新文献

There is a growing appreciation of the important role of small RNA (sRNA) molecules in post-transcriptional regulation of bacterial gene expression. sRNA transcripts are encoded within intergenic regions or in antisense orientation to mRNA transcripts, and sRNA regulation plays a central role in the response to stress stimuli encountered by pathogens during infection. We discuss the potential importance of sRNA in the pathogenesis of Mycobacterium tuberculosis.

Several mycobacteria are remarkably successful human pathogens that cause wellknown infections such as tuberculosis and leprosy or emerging diseases such as Buruli ulcer. On encountering the virulent mycobacteria, the host develops a strong immune response which is dedicated to combat the invasion while bacilli have evolved several strategies to counteract and adapt to this hostile environment. Being positioned at the bacterial surface, mycobacterial lipids contribute to the interplay between host and pathogen. This review will briefly discuss some unusual mycobacterial lipids that have been identified, focusing on their immunomodulatory properties.

The advent of high-throughput platforms for the interrogation of biological systems at the cellular and molecular levels has allowed living cells to be observed and understood at a hitherto unprecedented level of detail and has enabled the construction of comprehensive, predictive in silico models. Here, we review the application of such high-throughput, systems-biological techniques to mycobacteria – specifically to the pernicious human pathogen Mycobacterium tuberculosis (MTb) and its ability to survive in human hosts. We discuss the development and application of transcriptomic, proteomic, regulomic, and metabolomic techniques for MTb as well as the development and application of genome-scale in silico models. Thus far, systems-biological approaches have largely focused on in vitro models of MTb growth; reliably extending these approaches to in vivo conditions relevant to infection is a significant challenge for the future that holds the ultimate promise of novel chemotherapeutic interventions.

The control of tuberculosis (TB) in humans is heavily reliant on short course chemotherapy yet this intervention is increasingly menaced by widespread multi- and extensively drug resistant strains of Mycobacterium tuberculosis. New druggable targets and novel leads are required for TB drug discovery to develop compounds with greater potency, and that are less prone to acquired drug resistance. As such, the concept of blocking the secretion of virulence proteins and modulating their effect with small molecules has gained increasing attention in recent years. Here, we propose targeting the principal virulence determinant of M. tuberculosis, the ESX-1 protein secretion system and its downstream effects, to discover new drugs and augment the dwindling armoury of effective antitubercular agents.

Transmission of drug-resistant tuberculosis, especially multidrug-resistant tuberculosis and extensive drug-resistant tuberculosis is an important public health problem worldwide, particularly in high TB burden developing countries. DOTS does help by providing effective treatment but needs to be supplemented with aggressive case finding. A simple and efficient way to reduce the transmission of drug-resistant TB is urgently needed. Efficient rapid diagnostic techniques, aggressive case finding and improved patient management and optimized treatment need help to reduce community transmission of drug-resistant TB.

Mycobacterium tuberculosis has five resuscitation promoting factors (Rpfs) which have been implicated in virulence and resuscitation from dormancy, possibly through cleavage of the β-1,4 glycosidic bond in peptidoglycan. Several possibilities exist for the role of these factors in influencing bacterial population dynamics, during active and latent tuberculosis infection, by the stimulation of bacterial growth through re-modeling of peptidoglycan. As such, the Rpfs may represent an interesting new class of cell wall targets for tuberculosis drug discovery.

Mycobacterium tuberculosis is exposed to multiple genotoxic stresses during host infection. Although crucial for bacillary survival and strain evolution, including the emergence of drug resistance, the mechanisms governing genome maintenance and DNA damage tolerance in M. tuberculosis remain poorly understood. This review highlights evidence for the roles of the major DNA repair pathways in mycobacterial pathogenesis and considers their potential identification as targets for novel compounds, especially those designed to inhibit the evolution of resistance.