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Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis.

ABSTRACT: Tuberculosis (TB) is a life-threatening disease resulting in an estimated 10 million new infections and 1.8 million deaths annually, primarily in underdeveloped countries. The economic burden of TB has been estimated as approximately 12 billion USD annually in direct and indirect costs. Additionally, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB strains resulting in about 250?000 deaths annually are now widespread, increasing pressure on the identification of new anti-TB agents that operate by a novel mechanism of action. Chrysomycin A is a rare C-aryl glycoside first discovered over 60 years ago. In a recent high-throughput screen, we found that chrysomycin A has potent anti-TB activity, with minimum inhibitory concentration (MIC) = 0.4 ?g/mL against MDR-TB strains. However, chrysomycin A is obtained in low yields from fermentation of Streptomyces, and the mechanism of action of this compound is unknown. To facilitate the mechanism of action and preclinical studies of chrysomycin A, we developed a 10-step, scalable synthesis of the isolate and its two natural congeners polycarcin V and gilvocarcin V. The synthetic sequence was enabled by the implementation of two sequential C-H functionalization steps as well as a late-stage C-glycosylation. In addition, >10 g of the advanced synthetic intermediate has been prepared, which greatly facilitated the synthesis of 33 new analogues to date. The structure-activity relationship was subsequently delineated, leading to the identification of derivatives with superior potency against MDR-TB (MIC = 0.08 ?g/mL). The more potent derivatives contained a modified carbohydrate residue which suggests that further optimization is additionally possible. The chemistry we report here establishes a platform for the development of a novel class of anti-TB agents active against drug-resistant pathogens.

SUBMITTER: Wu F

PROVIDER: S-EPMC7318084 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis.

Wu Fan F Zhang Jing J Song Fuhang F Wang Sanshan S Guo Hui H Wei Qi Q Dai Huanqin H Chen Xiangyin X Xia Xuekui X Liu Xueting X Zhang Lixin L Yu Jin-Quan JQ Lei Xiaoguang X

ACS central science 20200504 6

Tuberculosis (TB) is a life-threatening disease resulting in an estimated 10 million new infections and 1.8 million deaths annually, primarily in underdeveloped countries. The economic burden of TB has been estimated as approximately 12 billion USD annually in direct and indirect costs. Additionally, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB strains resulting in about 250 000 deaths annually are now widespread, increasing pressure on the identification of new anti-TB agents ...[more]

PMID: 32607440

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Project description:RationaleMulti-drug-resistant tuberculosis (MDR-TB) poses a significant public health challenge to the control and successful eradication of TB globally. Suboptimal treatment outcomes are common among persons with MDR-TB necessitating a need to understand the contextual factors.ObjectiveWe determined the factors associated with unsuccessful TB treatment among persons with MDR-TB at a large TB Unit in Central Uganda.MethodsWe retrospectively reviewed medical records for all persons with MDR-TB at Mubende Regional Referral Hospital MDR-TB Clinic in Central Uganda. The patients were treated with either second-line, modified second-line, or individualized anti-TB regimens and completed treatment between January 2012 and October 2023. The primary outcome was unsuccessful TB treatment defined as death, treatment failure, or loss to follow-up and measured as a binary outcome. We used a multivariable binary logistic regression analysis to determine the factors independently associated with unsuccessful TB treatment at a 5 % statistical significance level. We reported the adjusted odds ratio (aOR) and the 95 % confidence interval (CI).Measurements and resultsWe analyzed data from 98 persons with MDR-TB who were aged 15-78 years (mean 36.4 ± 15.4 years). Of these, 40 (40.8 %) were cured, 25 (25.5 %) completed TB treatment, 1 (1.0 %) had treatment failure, 13 (13.3 %) died, and 19 (19.4 %) were lost to follow-up. Overall, 33 (33.7 %) participants had unsuccessful TB treatment which was associated with older age for a 1-year increase in age (aOR 1.05, 95 % CI 1.01-1.09), malnutrition-mid-upper arm circumference of <12.5 cm (aOR 2.99, 95 % CI 1.16-7.98), and previous TB treatment (aOR 0.28, 95 % CI 0.10-0.77).ConclusionUnsuccessful TB treatment is high among persons with MDR-TB at this TB Unit. It is more likely as age advances and when persons with MDR-TB have malnutrition, but less likely when they have been previously treated for TB. Therefore, interventions to improve treatment outcomes may be beneficial for persons with MDR-TB who are older, malnourished, and those newly diagnosed with the disease. For example, routine nutritional assessment and counseling, including nutritional support for malnourished persons with MDR-TB may be needed to optimize their TB treatment success.

Project description:INTRODUCTION:Isoniazid-resistant, rifampin susceptible tuberculosis (INHR-TB) is the most common form of drug resistant TB globally. Treatment of INHR-TB with standard first-line therapy is associated with high rates of multidrug resistant TB (MDR-TB). We modelled the potential impact of INHR-TB detection and appropriate treatment on MDR-TB prevalence. METHODS:A decision analysis model was developed to compare three different strategies for the detection of TB (AFB smear, Xpert MTB/RIF, and Line-Probe Assays (LPA)), combined with appropriate treatment. The population evaluated were patients with a globally representative prevalence of newly diagnosed, drug-susceptible (88.6%), isoniazid-resistant (7.3%), and multidrug resistant (4.1%) pulmonary TB. Our primary outcome was the proportion of patients with MDR-TB after initial attempt at diagnosis and treatment within a 2-year period. Secondary outcomes were the proportion of i) individuals with detected TB who acquired MDR-TB ii) individuals who died after initial attempt at diagnosis and treatment. RESULTS:After initial attempt at diagnosis and treatment, LPA combined with appropriate INHR-TB therapy resulted in a lower proportion of prevalent MDR-TB (1.61%; 95% Uncertainty Range (UR: 2.5th and 97.5th percentiles generated from 10 000 Monte Carlo simulation trials) 1.61-1.65), when compared to Xpert (1.84%; 95% UR 1.82-1.85) and AFB smear (3.21%; 95% UR 3.19-3.26). LPA also resulted in fewer cases of acquired MDR-TB in those with detected TB (0.35%; 95% UR 0.34-0.35), when compared to Xpert (0.67%; 95% UR 0.65-0.67) and AFB smear (0.68%; 95% UR 0.67-0.69). The majority of acquired MDR-TB arose from the treatment of INHR-TB in all strategies. Xpert-based strategies resulted in a lower proportion of death (2.89%; 95% UR 2.87-2.90) compared to LPA (2.93%; 95% UR 2.91-2.94) and AFB smear (3.21%; 95% UR 3.19-3.23). CONCLUSION:Accurate diagnosis and tailored treatment of INHR-TB with LPA led to an almost 50% relative decrease in acquired MDR-TB when compared with an Xpert MTB/RIF strategy. Continued reliance on diagnostic and treatment protocols that ignore INHR-TB will likely result in further generation of MDR-TB.

Project description:BackgroundPatients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.MethodsIn an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.ResultsA total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.ConclusionsThe combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

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Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis.

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Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis.

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