Lipophilic pyrazinoic acid amide and ester prodrugs

Simões, Marta Filipa; Valente, Emília; Gomez, Manuel; Anes, Elsa; Constantino, Luís

doi:10.1016/j.ejps.2009.02.012

Cited by 50 publications

(35 citation statements)

References 22 publications

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“…A more promising option is to develop prodrugs or other vehicles that liberate POA inside the bacillus (or perhaps within acidified phagosomes harboring bacilli), enabling more efficient concentration of POA in the bacteria (4,33), while reducing the potential for toxicity. Prodrugs of POA that do not depend on the PncA amidase for release of POA have been described (8,(34)(35)(36)(37)(38)(39). One challenge to development of such prodrugs, that is reinforced by the poor activity of systemically administered POA in our study, has been to develop prodrugs that are sufficiently stable in plasma but readily cleaved to release POA inside M. tuberculosis (39).…”

Section: Discussionmentioning

confidence: 99%

High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis

Lanoix

Tasneen

O'Brien

et al. 2016

Antimicrob Agents Chemother

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e Pyrazinamide (PZA) is a prodrug requiring conversion to pyrazinoic acid (POA) by an amidase encoded by pncA for in vitro activity. Mutation of pncA is the most common cause of PZA resistance in clinical isolates. To determine whether the systemic delivery of POA or host-mediated conversion of PZA to POA could circumvent such resistance, we evaluated the efficacy of orally administered and host-derived POA in vivo. Dose-ranging plasma and intrapulmonary POA pharmacokinetics and the efficacy of oral POA or PZA treatment against PZA-susceptible tuberculosis were determined in BALB/c and C3HeB/FeJ mice. The activity of host-derived POA was assessed in rabbits infected with a pncA-null mutant and treated with PZA. Median plasma POA values for the area under the concentration-time curve from 0 h to infinity (AUC 0 -ؕ ) were 139 to 222 g·h/ml and 178 to 287 g·h/ml after doses of PZA and POA of 150 mg/kg of body weight, respectively, in mice. Epithelial lining fluid POA concentrations in infected mice were comparable after POA and PZA administration. In chronically infected BALB/c mice, PZA at 150 mg/kg reduced lung CFU counts by >2 log 10 after 4 weeks. POA was effective only at 450 mg/kg, which reduced lung CFU counts by ϳ0.7 log 10 . POA had no demonstrable bactericidal activity in C3HeB/FeJ mice, nor did PZA administered to rabbits infected with a PZA-resistant mutant. Oral POA administration and host-mediated conversion of PZA to POA producing plasma POA exposures comparable to PZA administration was significantly less effective than PZA. These results suggest that the intrabacillary delivery of POA and that producing higher POA concentrations at the site of infection will be more effective strategies for maximizing POA efficacy.T he control of tuberculosis (TB) is jeopardized by the increasing prevalence of multidrug-resistant TB (MDR-TB) caused by strains which are resistant to at least rifampin (RIF) and isoniazid (INH) (1). Unfortunately, resistance to the other key sterilizing drug, pyrazinamide (PZA), is commonly present in MDR-TB isolates (2). Compounding this problem are the well-recognized challenges in performing PZA susceptibility testing, resulting in the common therapeutic conundrum of whether to include PZA in MDR-TB treatment regimens without certainty of its potential contribution (3). Whereas the mechanism of action of PZA remains partially unknown, the primary mechanism of PZA resistance in clinical isolates is well established (4, 5). Because PZA is a prodrug that requires conversion to pyrazinoic acid (POA) for its antimicrobial effect, mutations of the gene encoding the mycobacterial PncA amidase (pncA) result in PZA resistance (4-7). Approximately 78% of PZA-resistant isolates harbor mutations in pncA (3). However, since pncA mutations do not affect susceptibility to POA in vitro, direct administration of POA or delivery in a form that does not require PncA for the generation of POA inside Mycobacterium tuberculosis could circumvent this mechanism of resistance.The MIC of POA against M. tube...

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Section: Discussionmentioning

confidence: 99%

High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis

Lanoix

Tasneen

O'Brien

et al. 2016

Antimicrob Agents Chemother

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“…Activation of the prodrugs in M. avium and BCG homogenates. M. avium homogenate and BCG homogenate were prepared using the technique described for M. smegmatis (14,18). The incubation of the homogenate with prodrug was performed at 37°C in a total volume of 1,500 l. The concentration of substrate in incubation media was 1.2 ϫ 10 Ϫ4 M, and the protein concentration was 0.12 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

“…Microwell tissue culture plates were purchased from Nunc. Pyrazinamide and the esters of POA, namely, E-12 (n-dodecyl pyrazinoate), E-14 (n-tetradecyl pyrazinoate), and E-16 (n-hexadecyl pyrazinoate), were synthesized as described previously (14). They then were prepared in stock solutions of 8 mg/ml in dimethyl sulfoxide (DMSO), diluted in Middlebrook 7H9 medium containing ADC (albumin, dextrose, and catalase; oleic acid was not included, as it is toxic for mycobacteria at acidic pH [15]; Difco), and acidified to pH 5.9 (14).…”

Section: Methodsmentioning

confidence: 99%

“…In order to improve the stability of the POA esters, we designed and synthesized several long-chain esters, showing that esters with long alkoxy chains are particularly resistant to hydrolysis in the plasma (14). This fact suggested that it is possible to identify some POA ester prodrugs with increased resistance toward plasmatic hydrolysis.…”

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confidence: 99%

“…Moreover, resistant strains will hardly be selected, as the mechanism would no longer depend on a single gene point mutation. Esterases also exist in human plasma; therefore, these esters may be hydrolyzed before reaching their bacterial target, their active moiety (POA) being too polar for effective permeation into mycobacteria (12)(13)(14).…”

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confidence: 99%

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Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages

Pires

Valente

Simões

et al. 2015

Antimicrob Agents Chemother

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Although the amides did not present significant activity, the esters were active against sensitive mycobacteria at concentrations 5-to 10-fold lower than those of PZA. Here, we report that these POA derivatives possess antibacterial efficacy in vitro and ex vivo against several species and strains of Mycobacterium with natural or acquired resistance to PZA, including M. bovis and M. avium. Our results indicate that the resistance probably was overcome by cleavage of the prodrugs into POA and a long-chain alcohol. Although it is not possible to rule out that the esters have intrinsic activity per se, we bring evidence here that long-chain fatty alcohols possess a significant antimycobacterial effect against PZA-resistant species and strains and are not mere inactive promoieties. These findings may lead to candidate dual drugs having enhanced activity against both PZA-susceptible and PZA-resistant isolates and being suitable for clinical development.

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Analogs of the Antituberculous Agent Pyrazinamide Are Competitive Inhibitors of NADPH Binding to M. tuberculosis Fatty Acid Synthase I

Sayahi

Pugliese

Zimhony

et al. 2012

Chemistry & Biodiversity

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Analogs of pyrazinamide (=pyrazine-2-carboxamide; PZA), an essential component of short-course antituberculous chemotherapy, such as 5-chloropyrazinamide (5-Cl-PZA) act as competitive inhibitors of NADPH binding to purified mycobacterial fatty acid synthase I (FAS I) as shown by Saturation Transfer Difference (STD) NMR studies. In addition, pyrazinoic acid esters (POE) and 5-Cl-POE reversibly bind to FAS I with the relatively greater affinity of longer-chain esters for FAS I, clear from the STD amplification factors. The competitive binding of PZA and 5-Cl-PZA clearly illustrates that both agents bind FAS. In contrast to PZA, at low NADPH concentrations 5-Cl-PZA is a cooperative inhibitor of NADPH binding.

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Lipophilic pyrazinoic acid amide and ester prodrugs

Cited by 50 publications

References 22 publications

High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis

High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis

Esters of Pyrazinoic Acid Are Active against Pyrazinamide-Resistant Strains of Mycobacterium tuberculosis and Other Naturally Resistant Mycobacteria In Vitro and Ex Vivo within Macrophages

Analogs of the Antituberculous Agent Pyrazinamide Are Competitive Inhibitors of NADPH Binding to M. tuberculosis Fatty Acid Synthase I

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