Potential anti-TB investigational compounds and drugs with repurposing potential in TB therapy: a conspectus

Adeniji, Adetomiwa A.; Knoll, Kirsten Elke; Loots, Du Toit

doi:10.1007/s00253-020-10606-y

Cited by 33 publications

(20 citation statements)

References 185 publications

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“…The conventional anti-TB drugs have been in use for many decades and the need to broaden their palette is urgent, pushed by an increase in incidence of multidrug-resistant and extensively drug-resistant TB cases. The search for new treatment regimens has resulted in the identification of several candidates, including new compounds or repurposed drugs (1).…”

Section: Resultsmentioning

confidence: 99%

A High-content Screening Assay based on Automated Microscopy for Monitoring Antibiotic Susceptibility of Mycobacterium Tuberculosis Phenotypes

Kalsum

Andersson

Das

et al. 2021

Preprint

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Background Assays enabling efficient high throughput drug screening are necessary for the discovery of new anti-mycobacterial drugs. The purpose of our work was to develop and validate an assay based on live-cell imaging which can monitor growth of two distinct phenotypes of Mycobacterium tuberculosis and to test their susceptibility to commonly used TB drugs. Results Both planktonic and cording phenotypes were successfully monitored as fluorescent objects using the live-cell imaging system Incucyte S3, allowing collection of data describing distinct characteristics of aggregate size and growth. The quantification of changes in total area of aggregates was used to define IC50 and MIC values of selected TB drugs which revealed that the cording phenotype grew more rapidly and displayed a higher susceptibility to rifampicin. A checkerboard approach, testing pair-wise combinations of sub-inhibitory concentrations of drugs, revealed rifampicin, linezolid and pretomanid as superior in inhibiting growth of cording phenotype. Conclusion Our results emphasize the efficiency of using automated live-cell imaging and its potential in high-through put whole-cell screening to evaluate existing and search for novel antimycobacterial drugs.

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Section: Resultsmentioning

confidence: 99%

A High-content Screening Assay based on Automated Microscopy for Monitoring Antibiotic Susceptibility of Mycobacterium Tuberculosis Phenotypes

Kalsum

Andersson

Das

et al. 2021

Preprint

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“…Multidrug combination therapy approaches for TB treatment make it a candidate for possible drug-drug interactions (DDIs) or drugnutrient interactions (DNIs) (67), which subsequently may result in poor TB treatment outcomes and the emergence of drugresistant TB (68,69). Considering the recent interest and the prospects associated with the use of repurposed drugs and pharmaconutrients as an adjunct therapy in TB (35,(70)(71)(72), this study further reinforces the prospect for the use of n-3 LCPUFA # Data are reported as means ± SEM percentage of total fatty acids of n = 6 mice/group and representative of two independent experiments. Unpaired two-tailed t-tests were used to test the effects between groups.…”

Section: Discussionmentioning

confidence: 99%

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status

et al. 2021

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Populations at risk for tuberculosis (TB) may have a low n-3 polyunsaturated fatty acid (PUFA) status. Our research previously showed that post-infection supplementation of n-3 long-chain PUFA (LCPUFA) in TB without TB medication was beneficial in n-3 PUFA sufficient but not in low-status C3HeB/FeJ mice. In this study, we investigated the effect of n-3 LCPUFA adjunct to TB medication in TB mice with a low compared to a sufficient n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient (n-3FAD) or n-3 PUFA-sufficient (n-3FAS) diet for 6 weeks before TB infection. Post-infection at 2 weeks, both groups were switched to an n-3 LCPUFA [eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] supplemented diet and euthanized at 4- and 14- days post-treatment. Iron and anemia status, bacterial loads, lung pathology, lung cytokines/chemokines, and lung lipid mediators were measured. Following 14 days of treatment, hemoglobin (Hb) was higher in the n-3FAD than the untreated n-3FAS group (p = 0.022), whereas the n-3FAS (drug) treated control and n-3FAS groups were not. Pro-inflammatory lung cytokines; interleukin-6 (IL-6) (p = 0.011), IL-1α (p = 0.039), MCP1 (p = 0.003), MIP1- α (p = 0.043), and RANTES (p = 0.034); were lower, and the anti-inflammatory cytokine IL-4 (p = 0.002) and growth factor GMCSF (p = 0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that n-3 LCPUFA therapy in TB-infected mice, in combination with TB medication, may improve anemia of infection more in low n-3 fatty acid status than sufficient status mice. Furthermore, the low n-3 fatty acid status TB mice supplemented with n-3 LCPUFA showed comparatively lower cytokine-mediated inflammation despite presenting with lower pro-resolving lipid mediators.

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“…Possible antituberculosis mechanism of action manifested by coumarin derivatives implies cytochrome synthesis disruption, suppression of cell proliferation, macrophage activation, and kinase inhibitor [43]. The insertion of other substituents of interest like heterocyclic moieties and oximes, in the coumarin basic nucleus, could anticipate direction for synthesizing potential novel antitubercular lead compounds.…”

Section: Coumarin Lead Derivativesmentioning

confidence: 99%

Promising Lead Compounds in the Development of Potential Clinical Drug Candidate for Drug-Resistant Tuberculosis

et al. 2020

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According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state mycobacterium tuberculosis. To explore and identify the most potential antitubercular drug candidate among various reported compounds, we focused to highlight the promising lead derivatives of isoniazid, coumarin, griselimycin, and the antimicrobial peptides. The aim of the present review is to fascinate significant lead compounds in the development of potential clinical drug candidates that might be more precise and effective against drug-resistant tuberculosis, the world research looking for a long time.

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Potential anti-TB investigational compounds and drugs with repurposing potential in TB therapy: a conspectus

Cited by 33 publications

References 185 publications

A High-content Screening Assay based on Automated Microscopy for Monitoring Antibiotic Susceptibility of Mycobacterium Tuberculosis Phenotypes

A High-content Screening Assay based on Automated Microscopy for Monitoring Antibiotic Susceptibility of Mycobacterium Tuberculosis Phenotypes

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status

Promising Lead Compounds in the Development of Potential Clinical Drug Candidate for Drug-Resistant Tuberculosis

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