The antimycobacterial mechanism of pyrazinoic acid is. Design and characterization of inulin conjugate for improved. Pyrazinoic acid, the active form of the firstline antituberculosis drug pyrazinamide, decreased the proton motive force and respiratory atp synthesis rates in subcellular mycobacterial membrane assays. In view of the fact that m bovis remains susceptible to pyrazinoic acid, the ala440thr variant of rpsa, a reported target of the active antibiotic, is by definition susceptible to the drug. Pyrazinamide inhibits the eukaryoticlike fatty acid. In the same study, mycobacterium smegmatis which is not susceptible to pza was found to convert pza to pyrazinoic acid but, due to an active efflux mechanism, did not accumulate the metabolite. This article about a heterocyclic compound is a stub. Pyrazinamide is a pro drug which requires conversion to its active form of pyrazinoic acid poa by mtbc. Esters of pyrazinoic acid are active against pyrazinamide. Lipophilic pyrazinoic acid amide and ester prodrugs stability, activation and activity against m.
As pyrazinamideresistant strains exhibit low or none pyrazinamidase activity, it is proposed that the active form of pyrazinamide pza is pyrazinoic acid poa. Under acidic conditions of ph 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli. Review the molecular basis of resistance to isoniazid. The inhibitory effect of pyrazinoic acid on serine transport was more pro. Pyrazinamide may be bacteriostatic or bactericidal against mycobacterium tuberculosis depending on the concentration of the drug attained at the. Isoniazid acts by inhibiting the synthesis of mycolic acids through the nadhdependent. Simoes mf, valente e, gomez mj, anes e, constantino l. Pharmacokinetics and pharmacodynamics of pyrazinoic acid. Poisons and medicine are oftentimes the same substance. Further, this active form of pza inhibits the ribosomal proteins s1, which facilitates the transfer. Pharmacokinetics and pharmacodynamics of pyrazinoic acid in murine models of tuberculosis 8th international workshop on clinical pharmacology of tb drugs 17 september 2015, san diego, ca jeanphilippe lanoix, m. In m tuberculosis, an accumulation of intracellular poa occurs when the extracellular ph is acidic.
Poa ester prodrugs with increased resistance toward plasmatic. May, 2019 the plasma halflife may be prolonged in patients with impaired renal or hepatic function. Pdf tuberculosis tb is a disease caused mainly by infection of mycobacterium tuberculosis affecting more than ten million people around the world find. Bacterial strains carrying mutations in pyrazinamidase result in pyrazinamide resistance. Inhaled pyrazinoic acid esters for the treatment of tuberculosis. Through mutant selection on agar containing pyrazinoic acid poa, the bioactive form of the prodrug pyrazinamide pza, we recently showed that missense mutations in the aspartate decarboxylase pand and the unfoldase clpc1, and lossoffunction mutation of polyketide synthases mas and ppsae involved in phthiocerol dimycocerosate synthesis, cause resistance to poa and pza in mycobacterium.
To determine whether pyrazinoic acid inhibits the membrane transport of amino acids, we examined the effect of pyrazinoic acid on the uptake of l14 cserine at acid and neutral ph conditions. It disrupted membrane energetic and inhibited membrane transport function at acid ph in mycobacterium tuberculosis. Spray dried aerosol particles of pyrazinoic acid salts for. Exploring the pyrazinamide drug resistance mechanism of. Pyrazinamide is a pro drug converted to pyrazinoic acid by pyrazinamidase, an enzyme found in m. Pyrazinoic acid efflux rate in mycobacterium tuberculosis. Through mutant selection on agar containing pyrazinoic acid poa, the bioactive form of the prodrug pyrazinamide pza, we recently showed that missense mutations in the aspartate decarboxylase pand and the unfoldase clpc1, and lossoffunction mutation of polyketide synthases mas and ppsae involved in phthiocerol dimycocerosate synthesis, cause resistance. Finally, we highlight the peptide saap148, which has. Subsequently, pyrazinoic acid is hydroxylated to the main excretory compound. Pyrazinoic acid at 100 and 400 mgl inhibited the uptake of serine at acid ph 5. Pyrazinoic acid esters exhibit antimycobacterial activity probably to better. A firstline antimycobacterial drug is pyrazinamide pza, which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid poa.
Pdf synthesis and evaluation of a pyrazinoic acid prodrug. Its major influence is on the important cause of liver injury. Pdf synthesis and evaluation of a pyrazinoic acid prodrug in. Antimycobacterial agents, drug design, prodrugs, pyrazinamide, pyrazinoic acid, resistant tb. Whilst the importance of the pyrazinoic acid efflux rate to the susceptibility to pyrazinamide is recognized, its quantitative effect remains unknown. Sampson ma, phd, fhea, fbphs, in medical pharmacology and therapeutics fifth edition, 2018. Esters of pyrazinoic acid are active against pyrazinamideresistant. Pyrazinamide is used in combination with other drugs to treat tuberculosis. Media in category pyrazinoic acid the following 3 files are in this category, out of 3 total. Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours.
Also known as isonicotinic acid hydrazide, isoniazid is a pro drug that requires activation by the catalaseperoxidase enzyme katg, encoded by the katg gene, to exert its effect 23. It is postulated that the action of pyrazinoic acid poa, the active moiety of pyrazinamide, may be enhanced by local ph adjustment, when presented as a salt form. The pyrazinoic acid efflux rate may depend on multiple factors, including pyrazinamidase activity, intracellular pyrazinamidase concentration, and the efficiency of the efflux pump. External links human metabolome database hmdb0059734 chemspider 1018 bindingdb 50216541 chebi 711. Another compound, pyrazinoic acid poa, has been described for m. Pdf antisporothrix brasiliensis activity of different. Pyrazinamide fda prescribing information, side effects. Hayball 1, nikolai petrovsky 2,3 and sanjay garg 1.
It is proposed that pza interfere with the energetics and functions of the membrane zhang et al. Figure 1 is the active form of the pro drug pyrazinamide, which is one of the frontline drugs used in the treatment of tuberculosis. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. Short communication synthesis and evaluation of a pyrazinoic acid prodrug in mycobacterium tuberculosis joa.
Pyrazinamide pza is an essential first line antitubercular drug, which plays a crucial role in tuberculosis treatment. Hydrolyzed in the liver to major active metabolite, pyrazinoic acid. Esters of pyrazinoic acid are active against pyrazinamideresistant strains of. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinamide is a first line antituberculosis medication, but is used only in combination with other antituberculosis medications such as isoniazid or rifampin. Pyrazinamide, one of the drugs available in therapy of tuberculosis, is nowadays considered a bioprecursor of pyrazinoic acid, because resistant bacterias do not express an enzyme, pyrazinamidase, responsible by the conversion of pyrazinamide to pyrazinoic acid. Pyrazinamide is hydrolyzed in the liver to pyrazinoic acid, its major active metabolite. This enhanced kill correlated with accelerated depletion of cellular atp pools.
T2 disruption of mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. Barclay 1, ankit parikh 1, yunmei song 1, rosa chung 1, lixin wang 1, liang liu 1, john d. Introduction among the zoonotic diseases with importance in human and veterinary medicine, sporotrichosis should be highlighted due to the increasing reports in both human and animals. Pyrazinoic acid is hydroxylated to the main excretory product, 5hydroxypyrazinoic acid. Bacterial killing by bedaquiline and depletion of atp levels were also enhanced in combination with the efflux pump. Lipid biochemistry takes a stand against tuberculosis.
Pyrazinamide pyrazinamide dose, indications, adverse. Pyrazinamide is a prodrug and it undergoes hydrolysis and forms the active metabolite pyrazinoic acid. Issues in mycobacterium tuberculosis complex mtbc drug. The pza, which is considered as a pro drug needs an enzyme of mycobacterial pyrazinamidase pzase for its conversion into an active form pyrazinoic acid. Pza is valuable in tb control, because it becomes active in acid conditions and may kill bacteria inside the granuloma, while other drugs lose their activity under these conditions, but some mycobacterial strains are naturally resistant to pza. It is odorless and slowly affected by exposure to air and light. In vivoselected pyrazinoic acidresistant mycobacterium. Excreted in urine 70%, mainly by glomerular filtration. Antisporothrix brasiliensis activity of different pyrazinoic acid prodrugs. Pyrazinamide may be bacteriostatic or bactericidal against mycobacterium tuberculosis depending on the concentration of the drug attained at. Pyrazinamide is a pro drug that is cleaved to pyrazinoic acid by the mycobacterial enzyme pyrazinamidase. Structure, properties, spectra, suppliers and links for.
Poa was prepared as leucine poaleu and ammonium salts poanh4, spray dried and. Pyrazinamide pza is a prodrug requiring conversion to pyrazinoic acid poa by an amidase. Pza is a pro drug converted into pyrazinoic acid poa by the pyrazinamidase enzyme. Pyrazinoic acid efflux rate in mycobacterium tuberculosis is. High systemic exposure of pyrazinoic acid has limited. They are supplied as white, round, scored tablets debossed vp012 in containers of 60 tablets ndc 6174801206, in containers of 90 tablets ndc 6174801209, in containers of 100 tablets ndc 6174801201, in containers of 500 tablets ndc 6174801205, and in hospital unitdose. Inhaled pyrazinoic acid esters for the treatment of. Design and characterization of inulin conjugate for improved intracellular and targeted delivery of pyrazinoic acid to monocytes franklin a. Pyrazinoic acid also significantly lowered cellular atp levels in mycobacterium bovis bcg. In acid conditions, liberated pyrazinoic acid reenters m. Pyrazinamide tablets usp contain pyrazinamide 500 mg. Not known whether pyrazinamide crosses the placenta. Synthesis and antimycobacterial activity of pyrazinoic acid.
Halflife may be prolonged in patients with renal or hepatic. Nov 01, 2019 pyrazinoic acid is hydroxylated to the main excretory product, 5hydroxypyrazinoic acid. Design and characterization of inulin conjugate for. Pdf lipophilic pyrazinoic acid amide and ester prodrugs. Pyrazinamide pza was discovered during investigations of analogs of nicotinamide kushner et al. However, if a 30 per cent solution of trichloroacetic acid is used, instead of 10 per cent solution employed here, exchange of pyrazinoic. The antimycobacterial activity appears to depend on conversion of the drug to pyrazinoic acid. Pyrazinamide and its metabolites are excreted in the urine 70%, primarily via glomerular filtration. Pza constitutes a prodrug that in the mycobacterial cell is hydrolyzed to yield the active entity, pyrazinoic acid poa16. Pza is a pro drug converted into pyrazinoic acid poa. Drug resistance mechanisms in mycobacterium tuberculosis.
It is a colorless or white crystalline powder or white crystals. Here, we demonstrate that such poa ester prodrugs are active against. Pyrazinoic acid also called pyrazinecarboxylic acid or pyrazinic acid. Antibiotics 2014, 3 319 metabolicallyactive replicating bacilli. Pyrazinamide is associated with transient and asymptomatic elevations in serum aminotransferase levels and is a well known cause of clinically apparent, acute liver injury that can be severe and even fatal.
In one study, pyrazinoic acid remained outside of m. Synthesis and antimycobacterial activity of pyrazinoic. New watersoluble antiviral compounds also use ester aminoacid prodrugs to increase solubility with a bicyclic nucleoside subunit. Pharmacokinetics and pharmacodynamics of pyrazinoic acid in. Synthesis and evaluation of a pyrazinoic acid prodrug in m. There is currently no way to reimburse for the absence of liver function. It is freely soluble in water, sparingly soluble in alcohol and slightly soluble in chloroform and in ether. Synonyms not available unii 2wb23298sp cas number not available weight average. Approximately 70% of an oral dose is excreted in urine, mainly by glomerular filtration within 24 hours. Yet, the active derivative poa is not directly used to treat tb patients, because the bactericidal. Pyrazinamide and pyrazinoic acid derivatives directed to. Dec 23, 2019 hydrolyzed in the liver to major active metabolite, pyrazinoic acid. Use this link for bookmarking this species for future reference.
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