A combination screening to identify enhancers of para-aminosalicylic acid against Mycobacterium tuberculosis

Heo, Jinyeong; Koh, Dahae; Woo, Minjeong; Kwon, Doyoon; Falcão, Virgínia Carla de Almeida; Wood, Connor; Lee, Honggun; Kim, Kideok; Choi, Inhee; Jang, Jichan; Brodin, Priscille; Shum, David; Delorme, Vincent

doi:10.1038/s41598-022-08209-w

Cited by 5 publications

(3 citation statements)

References 31 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAS arrests the mycobacterial growth after incorporation in the folate synthesis pathway, leading to inhibition of the dihydrofolate reductase. 13 In the earliest trials, published in 1952, the SM + PAS combination improved the course of pulmonary tuberculosis in 78% of cases overall, but in only 59% of those with chronic forms of tuberculosis or previous treatment with either of these drugs. 14…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Management of Pulmonary Tuberculosis: A Century of Expert Opinions in Cecil Textbook of Medicine

Manu

Rogozea

2022

American Journal of Therapeutics

View full text Add to dashboard Cite

Background:Advances in drug therapy for pulmonary tuberculosis have had an extraordinary impact on the incidence of tuberculosis in the United States in the past century, which has decreased from 113/100,000 persons in 1920 to 2.2/100,000 in 2020. Modern treatments have contributed to a remarkable decrease in hospitalizations and mortality and have had a significant impact on the duration and severity of illness, quality of life, and work potential of affected persons.Study Question:What are the milestones of the changes in the expert approach to the pharmacological management of pulmonary tuberculosis in the past century?Study Design:To determine the changes in the experts' approach to the management of pulmonary tuberculosis, as presented in a widely used textbook in the United States.Data Sources:The chapters describing the management of pulmonary tuberculosis in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020.Results:In the preantibiotic era (1927–1943), the Cecil authors emphasized rest, good food, and fresh air as the treatment pillars for pulmonary tuberculosis. The modern era (1947–1971) recorded the discovery of all the drugs that are still used for the initial treatment, in the following order: streptomycin, para-aminosalicylic acid, isoniazid, pyrazinamide, ethambutol, cycloserine, kanamycin, ethionamide, capreomycin, and rifampin. In the postmodern era (1975–2020), therapeutic advances continued with trials of many drug combinations aimed at ameliorating the duration of treatment, drug resistance adverse effects, and poor the recent addition of fluoroquinolones, bedaquiline, and clofazimine.Conclusions:The pharmacological management of tuberculosis has remained archaic until the middle of the 20th century. Fundamental progress occurred in a very short period (1947–1971) and was because of the recognition of the antituberculous effect of many antibiotics and chemotherapy agents. The challenges created by mycobacterial infections resistant to multiple drugs remain and have prompted the addition of new drugs in the past decade.

show abstract

Section: Resultsmentioning

confidence: 99%

Pharmacological Management of Pulmonary Tuberculosis: A Century of Expert Opinions in Cecil Textbook of Medicine

Manu

Rogozea

2022

American Journal of Therapeutics

View full text Add to dashboard Cite

show abstract

“…Supplementary material Table 1 provides a detailed description of the basic concepts involved in CADD Ligand-based Virtual Screening ranks candidate drug molecules based upon their properties and how similar they are to existing active compounds (Motamen & Quinn, 2020). Molecular representations are used for input compounds to screen out a subset of active compounds from a pool of compounds of interest based on existing structure-activity information (Urbina et al, 2021) (Heo et al, 2022). Similarity and internal structure searching, quantitative-structure activity relationship (QSAR) and pharmacophore-based search are examples of ligand-based methods (Jankute et al, 2017).…”

Section: Screening Of Therapeutic Targets Using Machine Learning and ...mentioning

confidence: 99%

Advances in computational frameworks in the fight against TB: The way forward

Naidu

Nayak

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

Around 1.6 million people lost their life to Tuberculosis in 2021 according to WHO estimates. Although an intensive treatment plan exists against the causal agent, Mycobacterium Tuberculosis, evolution of multi-drug resistant strains of the pathogen puts a large number of global populations at risk. Vaccine which can induce long-term protection is still in the making with many candidates currently in different phases of clinical trials. The COVID-19 pandemic has further aggravated the adversities by affecting early TB diagnosis and treatment. Yet, WHO remains adamant on its “End TB” strategy and aims to substantially reduce TB incidence and deaths by the year 2035. Such an ambitious goal would require a multi-sectoral approach which would greatly benefit from the latest computational advancements. To highlight the progress of these tools against TB, through this review, we summarize recent studies which have used advanced computational tools and algorithms for—early TB diagnosis, anti-mycobacterium drug discovery and in the designing of the next-generation of TB vaccines. At the end, we give an insight on other computational tools and Machine Learning approaches which have successfully been applied in biomedical research and discuss their prospects and applications against TB.

show abstract

“…However, they had significant side effects and suffered from the development of drug resistance when taken independently. 48,49 In 1951, the implementation of isoniazid (Figure 1-5) as an anti-TB drug began the journey to modern TB treatment regimens. Today, it is still one of the most effective first-line drugs.…”

Section: Preventative Treatmentmentioning

confidence: 99%

Towards a New Class of Anti-Tuberculosis Drugs: Design and Synthesis of AnPRT TS Analogues

Mason¹

View full text Add to dashboard Cite

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacteria tuberculosis (Mtb). In 2021 over 10 million people were diagnosed with TB. It is the number two cause of death behind COVID-19, being attributed to 1.6 million deaths in 2021. Although TB is curable the current multidrug treatment regimens are lengthy, which leads to low adherence and unfavourable treatment outcomes. This has given rise to antibiotic resistance, with 170,000 cases confirmed to be resistant to at least one of the first-line drugs in 2021. The COVID-19 pandemic has also had a significant impact on the global TB burden. This highlights the need for a new class of anti-tuberculosis drugs to tackle this current health crisis. Tryptophan (Trp) is an amino acid that is important for the survival and virulence of Mtb. The Mtb Trp biosynthetic pathway is absent in mammals, therefore the inhibition of this pathway represents a great opportunity for the development of novel tuberculosis drugs. Our group is experienced in transition state analysis (TSA) techniques, which is a sophisticated and rational technique to design potent enzyme inhibitors. This is exemplified by Mundesine®, a drug used for the treatment of peripheral T-cell lymphoma in Japan. In pursuit of a new class of anti-tuberculosis drug candidates, a series of potential TS analogues of anthranilate phosphoribosyl transferase (AnPRT), an enzyme involved in Trp biosynthesis pathway, were designed and synthesised. For the synthesis of the first generation of compounds we used 5-O-tert-butyldimethylsilyl-1,N-dehydro-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-N-oxide-D-ribitol as a common intermediate. Seven targets were successfully isolated and the synthetic route leading to these targets has been optimised. These iminoribitol derivatives were then tested against the intended target AnPRT, using an enzyme-coupled assay. Unfortunately, the enzymatic assay revealed that the compounds tested displayed minimal inhibitory activity. Co-crystallisation with the enzyme and subsequent x-ray crystallography confirmed that this series of compounds did not bind in the active site of the enzyme. In order to facilitate entry into the active site, a more flexible second and third generation of acyclic phosphate and acyclic phosphonate derivatives were designed. The synthesis of the second generation of targets proved to be challenging and required several alterations to the initial proposed synthetic route. This resulted in the preparation of a single compound. The third generation required less optimisation. Although there were difficulties with the final purification, five compounds were successfully isolated. Evaluating the inhibitory activity of these compounds will assist in drawing structure activity relationships between our compounds and the enzyme, which can be used for the refinement of future generations of inhibitors.

show abstract

A combination screening to identify enhancers of para-aminosalicylic acid against Mycobacterium tuberculosis

Cited by 5 publications

References 31 publications

Pharmacological Management of Pulmonary Tuberculosis: A Century of Expert Opinions in Cecil Textbook of Medicine

Pharmacological Management of Pulmonary Tuberculosis: A Century of Expert Opinions in Cecil Textbook of Medicine

Advances in computational frameworks in the fight against TB: The way forward

Towards a New Class of Anti-Tuberculosis Drugs: Design and Synthesis of AnPRT TS Analogues

Contact Info

Product

Resources

About