Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm : Figure 1.

Chakraborty, Sumit; Rhee, Kyu Y.

doi:10.1101/cshperspect.a021147

Cited by 74 publications

(54 citation statements)

References 89 publications

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“…Some have discussed taking more of a mechanism-based approach to TB drug development [20] or a pathway-based approach to screening [58]. A recent opinion [91] has also laid out criteria for antituberculous hits and leads to ensure the quality of compounds, in particular focusing on the massive Global Health Innovative Technology Fund's high-throughput screen being undertaken in Japan against M. tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

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Learning from the past for TB drug discovery in the future

Mikušová

Ekins

2017

Drug Discovery Today

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Tuberculosis drug discovery has shifted in recent years from a primarily target-based approach to one that uses phenotypic high-throughput screens. As examples of this, through our EU-funded FP7 collaborations, New Medicines for Tuberculosis was target-based and our more-recent More Medicines for Tuberculosis project predominantly used phenotypic screening. From these projects we have examples of success (DprE1) and failure (PimA) going from drug to target and from target to drug, respectively. It is clear that we still have much to learn about the drug targets and the complex effects of the drugs on Mycobacterium tuberculosis. We propose a more integrated approach that learns from earlier drug discovery efforts that could help to move drug discovery forward.

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Section: Discussionmentioning

confidence: 99%

“…This discovery that catalysis rather than inhibition of an enzyme can be an important mechanism for targeting M. tuberculosis presents a new way of thinking about how we can develop drugs for this disease. It has been suggested that no single approach is sufficient for predicting the target or mechanism of an antibiotic [20]. …”

Section: Introductionmentioning

confidence: 99%

Learning from the past for TB drug discovery in the future

Mikušová

Ekins

2017

Drug Discovery Today

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“…The limitation of biochemical screening, however, is that the majority of enzyme inhibitors so identified lack activity against intact M. tuberculosis due to poor uptake, the sufficiency of residual enzyme activity for cell survival, intracellular metabolism, or redundant pathways (116). Translating biochemical screening hits to whole cell activity is hampered by using a binary readout of life/death of a bacterial cell as a surrogate to monitor target engagement (117). …”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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“…Historically speaking, nearly all clinically approved TB drugs emerged from empirical approaches that have since proven unproductive [9]. The need for new TB drugs has thus prompted concerted efforts to develop more rational approaches [10].…”

Section: The Rising Tide Of Antimicrobial Drug Resistancementioning

confidence: 99%

“…In the context of TB drug development, it may be of particular interest to note that many of the TB drugs in current clinical use and development are pro-drugs that undergo extensive biotransformation in Mtb [9,65]. Within this context, metabolomics have helped to identify N-methylation as a mechanism of drug resistance [55].…”

Section: Compound-based Drug Developmentmentioning

confidence: 99%

Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome

Jansen

Rhee

2017

Trends in Pharmacological Sciences

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Once considered a crowning achievement of modern drug development, tuberculosis (TB) chemotherapy has proven increasingly unable to keep pace with the spread of the pandemic and rise of drug resistance. Efforts to revive the TB drug development pipeline have, in the meantime, faltered. Closer analysis reveals key experimental deficiencies that have hindered our ability to ‘reverse engineer’ knowledge of antibiotic mechanism into rational drug development. Here, we discuss the emerging potential of metabolomics, the systems level study of small molecule metabolites, to help overcome these gaps and serve as a unique biochemical bridge between the phenotypic properties of chemical compounds and biological targets.

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Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm : Figure 1.

Cited by 74 publications

References 89 publications

Learning from the past for TB drug discovery in the future

Learning from the past for TB drug discovery in the future

Targeting Phenotypically TolerantMycobacterium tuberculosis

Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome

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