Impact of the host environment on the antitubercular action of pyrazinamide

Lamont, Elise A.; Baughn, Anthony D.

doi:10.1016/j.ebiom.2019.10.014

Cited by 24 publications

(13 citation statements)

References 120 publications

(151 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed condition-specific drug potencies consistent with previous reports, suggesting that the models we adapted for high-throughput drug response measurements may be predictive of outcomes in animals. For example, the activity of pyrazinamide in acidic and intracellular models and inactivity in the standard model (Table S2) was consistent with in vitro (45,46) and animal studies (47)(48)(49). We also observed pyrazinamide activity with lipid carbon sources, which has not been previously reported.…”

Section: Drug Combination Dose Response Measurementssupporting

confidence: 89%

Systematic measurement of combination drug landscapes to predictin vivotreatment outcomes for tuberculosis

Larkins-Ford

Greenstein

Van

et al. 2021

Preprint

View full text Add to dashboard Cite

A lengthy multidrug chemotherapy is required to achieve a durable cure in tuberculosis. Variation in Mycobacterium tuberculosis drug response is created by the differing microenvironments in lesions, which create different bacterial drug susceptibilities. To better realize the potential of combination therapy to shorten treatment duration, multidrug therapy design should deliberately explore the vast combination space. We face a significant scaling challenge in making systematic drug combination measurements because it is not practical to use animal models for comprehensive drug combination studies, nor are there well validated high-throughput in vitro models that predict animal outcomes. We hypothesized that we could both prioritize combination therapies and quantify the predictive power of various in vitro models for drug development using a dataset of drug combination dose responses measured in multiple in vitro models. We systematically measured M. tuberculosis response to all 2- and 3-drug combinations among ten antibiotics in eight conditions that reproduce lesion microenvironments. Applying machine learning to this comprehensive dataset, we developed classifiers predictive of multidrug treatment outcome in a mouse model of disease relapse. We trained classifiers on multiple mouse models and identified ensembles of in vitro models that best describe in vivo treatment outcomes. Furthermore, we found that combination synergies are less important for predicting outcome than metrics of potency. Here, we map a path forward to rationally prioritize combinations for animal and clinical studies using systematic drug combination measurements with validated in vitro models. Our pipeline is generalizable to other difficult-to-treat diseases requiring combination therapies.

show abstract

Section: Drug Combination Dose Response Measurementssupporting

confidence: 89%

Systematic measurement of combination drug landscapes to predictin vivotreatment outcomes for tuberculosis

Larkins-Ford

Greenstein

Van

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…This leads to a lethal alteration of membrane permeability; however, the exact mechanism by which this occurs is not yet known (3). It is important to note that other recent studies found that extracellular acid pH is not required in order for PZA/POA achieve its lethal effect (4,5,6). This confirms that the real mechanism of action of PZA is actually more complicated than previously thought, and further research is required.…”

Section: Introductionsupporting

confidence: 62%

EXPRESSION OFMycobacterium tuberculosisRpsA INMycobacterium smegmatisINCREASES SUSCEPTIBILITY TO PYRAZINAMIDE

Antiparra

Santos

Toledo

et al. 2020

Preprint

View full text Add to dashboard Cite

Pyrazinamide (PZA) is one of the most important drugs used in combined antituberculous therapy. After the drug enters Mycobacterium tuberculosis it is hydrolyzed by pyrazinamidase (PZAse) to the bactericidal molecule pyrazinoic acid (POA).Ribosomal protein S1 (RpsA) was recently identified as a possible target of PZA based on its binding activity to POA and capacity to inhibit trans-translation. However, its role is not completely understood. It has been proposed thatMycobacterium smegmatis RpsA is not capable of binding POA, unlike M. tuberculosis RpsA. This may be due to the different amino acid sequence in the carboxy-terminal region of the two molecules: in M. smegmatis RpsA it is much closer to the sites that may interact with POA than in M. tuberculosis RpsA. These differences could be contributing, along with the presence of highly active POA efflux, to the natural resistance to PZA in M. smegmatis. To further understand the mechanisms of action of PZA and the role of RpsA in PZA susceptibility, we evaluated the effect of complementing M. tuberculosis RpsA expression in M. smegmatis using pNIT mycobacterial non-integrative expression vector and then performed a PZA susceptibility test determining the minimum inhibitory concentration (MIC) of PZA. It was expected that chimeric ribosomes comprising M.tuberculosis RpsA may be present and may affect PZA susceptibility.Our results showed a reduction in PZA MIC in M. smegmatis complemented with overexpressed M. tuberculosis RpsA compared to non-overexpressed M. smegmatis (468 µg/mL and >7500 µg/mL respectively).

show abstract

“…Drugs with well-established sterilizing potency included rifampin, bedaquiline, and pyrazinamide. Pyrazinamide was excluded from in vitro analysis because its full activity requires in vivo conditions 27 . The well-established non-sterilizing drugs examined included isoniazid, streptomycin, and ethambutol.…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens

et al. 2021

View full text Add to dashboard Cite

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.

show abstract

Impact of the host environment on the antitubercular action of pyrazinamide

Cited by 24 publications

References 120 publications

Systematic measurement of combination drug landscapes to predictin vivotreatment outcomes for tuberculosis

Systematic measurement of combination drug landscapes to predictin vivotreatment outcomes for tuberculosis

EXPRESSION OFMycobacterium tuberculosisRpsA INMycobacterium smegmatisINCREASES SUSCEPTIBILITY TO PYRAZINAMIDE

Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens

Contact Info

Product

Resources

About