Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis

Young, Ellen; Perkowski, Ellen F.; Malik, Shaukat Iqbal; Hayden, Jennifer; Durham, Phillip G.; Zhong, Liping; Welch, John T.; Braunstein, Miriam; Hickey, Anthony

doi:10.1007/s11095-016-1974-5

Cited by 10 publications

(15 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An alternative therapeutic strategy for these clinical scenarios might be to deliver POA or POA salts to the lung by aerosol, as suggested by some investigators (25,26). There is some recent evidence for the efficacy of this approach in a guinea pig model (27).…”

Section: Discussionmentioning

confidence: 99%

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

Naftalin

Verma

Gurumurthy

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Coadministering pyrazinamide (PZA) with the xanthine oxidase inhibitor allopurinol increases systemic levels of the active metabolite, pyrazinoic acid (POA), but the effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10 or 25 mg/kg of body weight) at the first visit and the same dose 7 days later, coadministered with allopurinol (100 mg daily; 2 days before to 1 day after the PZA dose). Blood was drawn at intervals until 48 h after each PZA dose, and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with and estimating the change in bacterial CFU after 72 h of incubation. Allopurinol increased the POA area under the concentration-time curve from 0 to 8 h (AUC) (18.32 h · μg/ml versus 24.63 h · μg/ml for PZA alone versus PZA plus allopurinol) ( < 0.001) and its peak plasma concentration () (2.81 μg/ml versus 4.00 μg/ml) ( < 0.001). There was no effect of allopurinol on mean cumulative WBA (0.01 ± 0.02 ΔlogCFU versus 0.00 ± 0.02 ΔlogCFU for PZA alone versus PZA plus allopurinol) ( = 0.49). Higher systemic POA levels were associated with greater WBA levels ( < 0.001), but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA despite a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Coadministration of allopurinol does not appear to be a useful strategy for increasing the efficacy of PZA in clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT02700347.).

show abstract

Section: Discussionmentioning

confidence: 99%

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

Naftalin

Verma

Gurumurthy

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Groups of six guinea pigs were placed in a custom-built nose only exposure chamber [ 15 , 52 ]. The same exposure chamber was used to disperse the PDP (PAE and POA combination dry powder) or PAE nebulized formulations, each in five equal doses, totaling 100mg, spread out over 20 min.…”

Section: Methodsmentioning

confidence: 99%

“…This dose is comparable to the 112mg dose of dry powder tobramycin currently used to treat Pseudomonas aeruginosa in Cystic Fibrosis patients [ 59 ]. The nebulized PAE dose used was equivalent to the one used previously [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…We recently tested the efficacy of PAE aerosols, delivered as an aqueous dispersion from a nebulizer, combined with oral rifampicin (R) in treating M . tuberculosis infected guinea pigs and observed a reduction in bacterial burden compared to untreated animals [ 15 ]. Motivated by these past results and the advantageous properties of DPIs, here we tested efficacy of a dry powder combination of POA and a PAE in treating TB in guinea pigs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis

et al. 2018

Self Cite

View full text Add to dashboard Cite

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.

show abstract

“…3 Ester-based prodrugs increase the oral bioavailability of TB therapeutics in preclinical studies, and potentially offer additional benefits over other prodrug strategies. For example, pyrazinoic acid esters have been found to be effective against pyrazinamide-resistant strains of M. tuberculosis , 10–14 with some compounds demonstrating dual effects through inhibition by both the masked drug and the masking group itself. 15 A drawback to ester-prodrugs is the assumption that nonspecific human hydrolases will remove any ester protecting groups prior to cell internalization, removing the additional therapeutic selectivity of the ester-prodrug.…”

mentioning

confidence: 99%

Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity

Larsen

Stephens

Clarke

et al. 2017

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

M. tuberculosis; contains an unusually high number of serine hydrolases by proteome percentage compared to other common bacteria or humans. This letter describes a method to probe the global substrate specificity of mycobacterial serine hydrolases with ester-protected prodrugs of ethambutol, a first-line antibiotic treatment for TB. These compounds were synthesized directly from ethambutol using a selective o-acylation to yield products in high yield and purity with minimal workup. A library of derivatives was screened against M. smegmatis, a non-infectious model for M. tuberculosis, which displayed significantly lowered biological activity compared to ethambutol. Incubation with a general serine hydrolase reactivated each derivative to near-ethambutol levels, demonstrating that esterification of ethambutol should provide a simple screen for mycobacterial hydrolase activity.

show abstract

Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis

Abstract: The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.

Cited by 10 publications

References 47 publications

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis

Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity

Contact Info

Product

Resources

About