Rifampin isoniazid pyrazinamide: Difference between revisions

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{{drugbox
__NOTOC__
| IUPAC_name = pyridine-4-carbohydrazide
{{Rifampin isoniazid pyrazinamide}}
| image = Isoniazid skeletal.svg
{{CMG}}; {{AE}} {{chetan}}
| width =
| CAS_number = 54-85-3
| ATC_prefix = J04
| ATC_suffix = AC01
| ATC_supplemental =
| PubChem = 3767
| DrugBank = APRD01055
| C=6 | H=7 | N=3 | O=1
| molecular_weight = 137.139 g/mol
| bioavailability =
| protein_bound = Very low (0-10%)
| metabolism = liver; CYP450: 2C19, 3A4 inhibitor
| elimination_half-life = 0.5-1.6h (fast acetylators), 2-5h (slow acetylators)
| excretion = urine (primarily), feces
| pregnancy_category = C
| legal_status = prescription only (US)
| routes_of_administration = oral, intramuscular, intravenous }}
{{SI}}


==Overview==


'''Isoniazid''' is also called '''isonicotinyl hydrazine''' or '''INH'''.  Isoniazid is a first-line antituberculous medication used in the prevention and treatment of [[tuberculosis]]. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
===Rifampin===


Isoniazid is used in the treatment of mycobacterial infection. It was discovered in 1952, when for the first time, a cure for tuberculosis was considered reasonable. It is available in tablet, syrup, and injectable forms (given intramuscularly or intravenously). Isoniazid is available world-wide, is inexpensive to produce and is generally well tolerated.
Rifampin ([[United States Adopted Name|USAN]]) or Rifampicin ([[International Nonproprietary Name|INN]]) is a [[bactericidal]] [[antibiotic]] drug of the [[rifamycin]] group.<ref name="isbn0-07-142290-0">{{cite book |author=Masters, Susan B.; Trevor, Anthony J.; Katzung, Bertram G. |title=Katzung & Trevor's pharmacology |publisher=Lange Medical Books/McGraw Hill, Medical Pub. Division |location=New York |year=2005 |pages= |isbn=0-07-142290-0 |oclc= |doi= |accessdate=}}</ref>


==Mechanism of action==
Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent [[RNA polymerase]].
Isoniazid is a [[prodrug]] and must be activated by bacterial catalase.  It is activated by catalase-peroxidase enzyme katG to form isonicotinic acyl anion or radical. These forms will then react with a [[NADH]] radical or anion to form isonicotinic acyl-NADH complex. This complex will bind tightly to ketoenoylreductase known as InhA and prevents access of the natural enoyl-AcpM substrate. This mechanism inhibits the synthesis of [[mycolic acid]] in the [[mycobacterium|mycobacterial]] cell wall.


Isoniazid reaches therapeutic concentrations in serum, [[cerebrospinal fluid]] (CSF), and within caseous granulomas.  Isoniazid is metabolized in the liver via [[acetylation]].  There are two forms of the enzyme responsible for acetylation, so that some patients metabolize the drug quicker than others.  Hence, the [[half-life]] is [[Bimodal_distribution|bimodal]] with peaks at 1 hour and 3 hours in the US population. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of [[renal failure]].
It is a semisynthetic compound derived from ''Amycolatopsis rifamycinica '' (formerly known as ''Amycolatopsis mediterranei'' and ''Streptomyces mediterranei'').<ref>{{cite journal|author=Sensi P, Margalith P, Timbal MT|title=Rifomycin, a new antibiotic—preliminary report|journal=Farmaco Ed Sci|year=1959|volume=14|pages=146–147}}</ref> Rifampicin may be abbreviated '''R''', '''RMP''', '''RA''', '''RF''', or '''RIF''' (US).


Isoniazid is [[bactericidal]] to rapidly-dividing [[mycobacterium|mycobacteria]], but is [[bacteriostatic]] if the mycobacterium is slow-growing.
In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in [[Milan]], Italy. There, a research group headed by Prof. Piero Sensi (1920-) and Dr. Maria Teresa Timbal (1925 - 1969) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story ''[[Rififi]]'' (about a jewel heist and rival gangs),<ref name="BMJ">{{cite web |url=http://www.bmj.com/cgi/content/extract/319/7215/972 |title=When I Use a Word . . .I Mean It |accessdate=2009-07-10|work=British Medical Journal 1999;319(7215):972 (9 October)}}</ref> they decided to call these compounds "rifamycins". After two years of attempts to obtain more stable semisynthetic products, a new molecule with high efficacy and good tolerability was produced in 1959 and was named "rifampicin".


==Dosing==
Rifampicin is also known as rifaldazine, R/AMP, rofact (in Canada), and rifampin in the United States. There are various types of rifamycins from which this is derived, but the rifampicin form, with a [[piperazine|4-methyl-1-piperazinaminyl]] group, is by far the most clinically effective.
The standard dose of isoniazid is 3-5mg/kg/day (max 300mg daily).
When prescribed intermittently (twice or thrice weekly) the dose is 15mg/kg (max 900mg daily).


==Side effects==
===Isoniazid===
Adverse reactions include [[rash]], abnormal [[liver function tests]], [[hepatitis]], [[sideroblastic anemia]], [[peripheral neuropathy]], mild [[central nervous system]] (CNS) effects, and drug [[interaction]]s resulting in increased [[phenytoin]] (Dilantin) or [[disulfiram]] (Antabuse) levels.


[[Peripheral neuropathy]] and [[Central nervous system|CNS]] effects are associated with the use of isoniazid and are due to [[pyridoxine]] (vitamin B6) depletion, but are uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., [[diabetes]], [[uremia]], [[alcoholism]], [[malnutrition]], [[HIV]]-infection), as well as [[pregnant]] women and persons with a [[seizure]] disorder, may be given [[pyridoxine]] (vitamin B6) (10-50 mg/day) with isoniazid.
Isoniazid, also known as isonicotinylhydrazine (INH), is an [[organic compound]] that is the first-line medication in prevention and treatment of [[tuberculosis]]. The compound was first synthesized in the early 20th century,<ref>{{Cite journal|author=Meyer H, Mally J|title=On hydrazine derivatives of pyridine carbonic acids|journal=Monatshefte Chemie verwandte Teile anderer Wissenschaften|volume=33|pages=393&ndash;414|doi = 10.1007/BF01517946|language=German|year=1912}}[http://springerlink.metapress.com/content/p7145p063227623j/fulltext.pdf PDF fulltext]</ref> but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug<ref>{{Cite journal|journal=Lancet|volume=373|issue=9670|pages=1148&ndash;1149|year=2009
|doi=10.1016/S0140-6736(09)60559-6|title=Fourth-generation fluoroquinolones in tuberculosis|author=Hans L Riede|pmid=19345815}}</ref> (the most prominent one being Roche, which launched its version, [http://www.rocheusa.com/about/history.html Rimifon], in 1952). The drug was first tested at [[Many Farms, Arizona|Many Farms]], a [[Navajo Nation|Navajo]] community, due to the Navajo reservation's dire tuberculosis problem and the fact that the population was [[Naïveté|naïve]] with respect to [[streptomycin]], the main tuberculosis treatment at the time.<ref>{{cite journal|last=Jones|first=David|title=The Health Care Experiments at Many Farms: The Navajo, Tuberculosis, and the Limits of Modern Medicine, 1952-1962|journal=Bulletin of the History of Medicine|year=2002|volume=76|issue=4|pages=749–790}}</ref> With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.


Hepatoxicity can be avoided with close clinical monitoring of the patient, specifically nausea, vomiting, abdominal pain and appetite.
===Pyrazinamide===


Headache, poor concentration, poor memory and depression have all been associated with isoniazid use.  The frequency of these side effects is not known, and the association with isoniazid is not well validated.  The presence of these symptoms is not frequently disabling and is certainly ''not'' a reason to stop treatment with isoniazid;  the patient should be strongly encouraged to continue treatment despite these symptoms.  It must be explained to the patient that the harm done from not taking isoniazid far outweighs the problems arising from these symptoms.
Pyrazinamide is a [[drug]] used to treat [[tuberculosis]].  The drug is largely [[bacteriostatic]], but can be [[bacteriocidal]] on actively replicating tuberculosis [[bacteria]].


INH therapy will decrease the efficacy of hormonal birth control when combined with Rifampin.
==Category==


==Synonyms and abbreviations==
Antimycobacterial
* Isonicotinyl hydrazine
* Isonicotinic acid hydrazide
* INH
* H (for "hydrazide", and also the [[World Health Organisation|WHO]] standard abbreviation)


==Wikipedia links==
==US Brand Names==
*[[Tuberculosis treatment]]
*[[Tuberculosis]]
*''[[Mycobacterium tuberculosis]]''


==References==
RIFATER<sup>®</sup>
*[http://www.cdc.gov/nchstp/tb/pubs/corecurr/default.htm Core Curriculum on Tuberculosis (2000)] Division of Tuberculosis Elimination, Centers for Disease Control and Prevention
 
==FDA Package Insert==
 
'''  [[Rifampin isoniazid pyrazinamide description|Description]]'''
'''| [[Rifampin isoniazid pyrazinamide clinical pharmacology|Clinical Pharmacology]]'''
'''| [[Rifampin isoniazid pyrazinamide microbiology|Microbiology]]'''
'''| [[Rifampin isoniazid pyrazinamide indications and usage|Indications and Usage]]'''
'''| [[Rifampin isoniazid pyrazinamide contraindications|Contraindications]]'''
'''| [[Rifampin isoniazid pyrazinamide warnings and precautions|Warnings and Precautions]]'''
'''| [[Rifampin isoniazid pyrazinamide adverse reactions|Adverse Reactions]]'''
'''| [[Rifampin isoniazid pyrazinamide overdosage|Overdosage]]'''
'''| [[Rifampin isoniazid pyrazinamide clinical studies|Clinical Studies]]'''
'''| [[Rifampin isoniazid pyrazinamide dosage and administration|Dosage and Administration]]'''
'''| [[Rifampin isoniazid pyrazinamide how supplied|How Supplied]]'''
'''| [[Rifampin isoniazid pyrazinamide labels and packages|Labels and Packages]]'''
 
==Mechanisms of Action==
 
===Rifampin===
 
Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent [[RNA polymerase]].<ref name="Calvori">{{cite journal |author=Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. |journal=Nature |title=Effect of rifamycin on protein synthesis |volume=207 |pages=417–8 |year=1965 |doi=10.1038/207417a0 |pmid=4957347 |issue=995}}</ref>
 
Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides ("steric-occlusion" mechanism).<ref name="Campbell">{{cite journal|author=Campbell, E.A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., Darst, S.A.|year=2001|title=Structural mechanism for rifampicin inhibition of bacterial RNA polymerase|journal=Cell|volume=104|issue=6|pages=901–12|pmid=11290327|doi=10.1016/S0092-8674(01)00286-0}}</ref><ref name="Feklistov">{{cite journal|author=Feklistov, A., Mekler, V., Jiang, Q., Westblade, L.F., Irschik, H., Jansen, R., Mustaev, A., Darst, S.A., [[Richard H. Ebright|Ebright, R.H.]]|year=2008|title=Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center|journal=Proc Natl Acad Sci USA|volume=105|issue=39|pages=14820–5|pmid=18787125|doi=10.1073/pnas.0802822105|pmc=2567451}}</ref>
 
Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.<ref name=Feklistov/>  Resistant mutations map to the ''[[rpoB]]'' gene, encoding RNA polymerase beta subunit.
 
===Isoniazid===
 
Isoniazid is a [[prodrug]] and must be activated by a bacterial catalase-peroxidase enzyme that in ''M. tuberculosis'' is called KatG.<ref>{{Cite journal|author=Suarez J, Ranguelova K, Jarzecki AA, ''et al.'' |title=An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG) |journal=The Journal of Biological Chemistry |volume=284 |issue=11 |pages=7017–29 |year=2009 |month=March |pmid=19139099 |doi=10.1074/jbc.M808106200 |pmc=2652337}}</ref>  KatG couples the isonicotinic acyl with [[NADH]] to form isonicotinic acyl-NADH complex. This complex binds tightly to the [[enoyl-acyl carrier protein reductase]] known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of [[fatty acid synthase]]. This process inhibits the synthesis of [[mycolic acid]], required for the [[mycobacterium|mycobacterial]] cell wall. A range of radicals are produced by KatG activation of isoniazid, including [[nitric oxide]],<ref>{{Cite journal|author=Timmins GS, Master S, Rusnak F, Deretic V |title=Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis |journal=Antimicrobial Agents and Chemotherapy |volume=48 |issue=8 |pages=3006–9 |year=2004 |month=August |pmid=15273113 |pmc=478481 |doi=10.1128/AAC.48.8.3006-3009.2004}}</ref> which has also been shown to be important in the action of another antimycobacterial prodrug [[PA-824]].<ref>{{Cite journal|author=Singh R, Manjunatha U, Boshoff HI, ''et al.'' |title=PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release |journal=Science |volume=322 |issue=5906 |pages=1392–5 |year=2008 |month=November |pmid=19039139 |doi=10.1126/science.1164571 |pmc=2723733}}</ref>
 
Isoniazid is [[bactericidal]] to rapidly dividing [[mycobacterium|mycobacteria]], but is [[bacteriostatic]] if the mycobacteria are slow-growing.<ref>{{cite pmid|19686043}}</ref>
 
Isoniazid inhibits the [[P450 system]].<ref>{{Cite book|title=Pharmacology, Harvey 4th edition|date=November 2009}}</ref>


See Chapter 6, Treatment of LTBI Regimens - [http://www.cdc.gov/nchstp/tb/pubs/corecurr/Chapter6/Chapter_6_Regimens.htm Isoniazid]
===Pyrazinamide===
<br>See Chapter 7 - Treatment of TB Disease Monitoring - [http://www.cdc.gov/nchstp/tb/pubs/corecurr/Chapter7/Chapter_7_Monitoring.htm Adverse Reactions to First-Line TB Drugs - Isoniazid]
<br>See Table 5 [http://www.cdc.gov/nchstp/tb/pubs/corecurr/Tables/table5.htm First-Line Anti-TB Medications]


*[http://www.aafp.org/afp/980215ap/romero.html Isoniazid Overdose: Recognition and Management] American Family Physician 1998 Feb 15
Pyrazinamide is a [[prodrug]] that stops the growth of ''[[Mycobacterium tuberculosis]]''.


{{Antimycobacterials}}
Pyrazinamide diffuses into ''M. tuberculosis'', where the enzyme pyrazinamidase converts pyrazinamide to the active form [[pyrazinoic acid]].  Under acidic conditions, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate.  The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.<ref name="pmid12701830">{{cite journal |author=Zhang Y, Mitchison D |title=The curious characteristics of pyrazinamide: a review |journal=Int. J. Tuberc. Lung Dis. |volume=7 |issue=1 |pages=6–21 |year=2003 |month=January |pmid=12701830 |doi= |url=http://openurl.ingenta.com/content/nlm?genre=article&issn=1027-3719&volume=7&issue=1&spage=6&aulast=Zhang}}</ref>


[[Category:Antibiotics]]
Pyrazinoic acid was thought to inhibit the enzyme [[fatty acid synthase]] (FAS) I, which is required by the bacterium to synthesise [[fatty acid]]s<!--
[[Category:Hydrazines]]
--><ref name="Zimhony2000">{{cite journal | author=Zimhony O, Cox JS, Welch JT, Vilchèze C,  Jacobs WR | title=Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of ''Mycobacterium tuberculosis'' | journal=Nature Medicine | year=2000 | volume=6 | issue=9 | pages=1043–47 | pmid=10973326 | url=http://www.nature.com/nm/journal/v6/n9/abs/nm0900_1043.html;jsessionid=AFEEF16483CA23196C7729EBE644297C | doi=10.1038/79558 | format=abstract }}</ref> although this has been discounted.<ref name="Boschoff2002">{{cite journal | author= Boshoff HI,  Mizrahi V, Barry CE | title=Effects of Pyrazinamide on Fatty Acid Synthesis by Whole Mycobacterial Cells and Purified Fatty Acid Synthase I | journal=Journal of Bacteriology| year=2002 | volume=184 | issue=8 | pages=2167–72 | doi = 10.1128/JB.184.8.2167-2172.2002 | pmid= 11914348 | pmc= 134955 }}</ref> It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids.<ref>Zimhony O, Vilcheze C, Arai M, Welch J, Jacobs WR pi. Pyrazinoic acid and its n'Propyl Ester Inhibit Fatty Acid Synthase I in Replicating Tubercle Bacilli. Antimicrob Agents Chemother. 2007 51 752-754
[[Category:Prodrugs]]
</ref> This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of  pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.<ref>Ngo SC., Zimhony O, Chung WJ Sayahi, H, Jacobs WR. and JT. Welchpi.  Inhibition of  Isolated Mycobacterium tuberculosis Fatty Acid Synthase I by Pyrazinamide Analogs. Antimicrob Agents Chemother AntimicrobAgents Chemother. 2007;  1 2430-5</ref> Pyrazinoic acid binds to the ribosomal protein S1 (RpsA) and inhibits [[Transfer-messenger_RNA#Trans-translation|trans-translation]]. This may explain the ability of the drug to kill dormant mycobacteria.<ref name="pmid21835980">{{cite journal| author=Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE et al.| title=Pyrazinamide inhibits trans-translation in ''Mycobacterium tuberculosis'' | journal=Science | year= 2011 | volume=333  | issue=6049  | pages=1630–1632  | pmid=21835980 | doi=10.1126/science.1208813 }} </ref>
[[Category:Pyridines]]
[[Category:Tuberculosis]]


Mutations in the [[pncA]] gene, which encodes a pyrazinamidase, is responsible for the appearance of most pyrazinamide resistant ''M. tuberculosis'' strains.<ref name=Scorpio1996>{{cite journal | author=Scorpio A, Zhang Y | title=Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus | journal=Nature Medicine | year=1996 | volume=2 | pages=662–7 | pmid=8640557 | doi=10.1038/nm0696-662 | issue=6 }}</ref>  A few pyrazinamidase resistant strains with mutations in the ''rpsA'' gene have also been identified.<ref name="pmid21835980"/>


==References==


[[ar:إيزونيازيد]]
{{Reflist|2}}
[[de:Isoniazid]]
[[es:Isoniacida]]
[[fa:ایزونیازید]]
[[fr:Isoniazide]]
[[nl:Isoniazide]]
[[nn:Isoniazid]]
[[pl:Izoniazyd]]


{{WH}}
[[Category:Antibiotics]]
{{WS}}
[[Category:Wikinfect]]

Latest revision as of 16:02, 3 January 2014

Rifampin Isoniazid Pyrazinamide
RIFATER ® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Overdosage
Clinical Studies
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]

Overview

Rifampin

Rifampin (USAN) or Rifampicin (INN) is a bactericidal antibiotic drug of the rifamycin group.[1]

Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.

It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei).[2] Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US).

In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Prof. Piero Sensi (1920-) and Dr. Maria Teresa Timbal (1925 - 1969) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs),[3] they decided to call these compounds "rifamycins". After two years of attempts to obtain more stable semisynthetic products, a new molecule with high efficacy and good tolerability was produced in 1959 and was named "rifampicin".

Rifampicin is also known as rifaldazine, R/AMP, rofact (in Canada), and rifampin in the United States. There are various types of rifamycins from which this is derived, but the rifampicin form, with a 4-methyl-1-piperazinaminyl group, is by far the most clinically effective.

Isoniazid

Isoniazid, also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line medication in prevention and treatment of tuberculosis. The compound was first synthesized in the early 20th century,[4] but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug[5] (the most prominent one being Roche, which launched its version, Rimifon, in 1952). The drug was first tested at Many Farms, a Navajo community, due to the Navajo reservation's dire tuberculosis problem and the fact that the population was naïve with respect to streptomycin, the main tuberculosis treatment at the time.[6] With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.

Pyrazinamide

Pyrazinamide is a drug used to treat tuberculosis. The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria.

Category

Antimycobacterial

US Brand Names

RIFATER®

FDA Package Insert

Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages

Mechanisms of Action

Rifampin

Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.[7]

Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides ("steric-occlusion" mechanism).[8][9]

Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.[9] Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.

Isoniazid

Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.[10] KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide,[11] which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.[12]

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.[13]

Isoniazid inhibits the P450 system.[14]

Pyrazinamide

Pyrazinamide is a prodrug that stops the growth of Mycobacterium tuberculosis.

Pyrazinamide diffuses into M. tuberculosis, where the enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. Under acidic conditions, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.[15]

Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids[16] although this has been discounted.[17] It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids.[18] This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.[19] Pyrazinoic acid binds to the ribosomal protein S1 (RpsA) and inhibits trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.[20]

Mutations in the pncA gene, which encodes a pyrazinamidase, is responsible for the appearance of most pyrazinamide resistant M. tuberculosis strains.[21] A few pyrazinamidase resistant strains with mutations in the rpsA gene have also been identified.[20]

References

  1. ↑ Masters, Susan B.; Trevor, Anthony J.; Katzung, Bertram G. (2005). Katzung & Trevor's pharmacology. New York: Lange Medical Books/McGraw Hill, Medical Pub. Division. ISBN 0-07-142290-0.
  2. ↑ Sensi P, Margalith P, Timbal MT (1959). "Rifomycin, a new antibiotic—preliminary report". Farmaco Ed Sci. 14: 146–147.
  3. ↑ "When I Use a Word . . .I Mean It". British Medical Journal 1999;319(7215):972 (9 October). Retrieved 2009-07-10.
  4. ↑ Meyer H, Mally J (1912). "On hydrazine derivatives of pyridine carbonic acids". Monatshefte Chemie verwandte Teile anderer Wissenschaften (in German). 33: 393&ndash, 414. doi:10.1007/BF01517946.PDF fulltext
  5. ↑ Hans L Riede (2009). "Fourth-generation fluoroquinolones in tuberculosis". Lancet. 373 (9670): 1148&ndash, 1149. doi:10.1016/S0140-6736(09)60559-6. PMID 19345815.
  6. ↑ Jones, David (2002). "The Health Care Experiments at Many Farms: The Navajo, Tuberculosis, and the Limits of Modern Medicine, 1952-1962". Bulletin of the History of Medicine. 76 (4): 749–790.
  7. ↑ Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. (1965). "Effect of rifamycin on protein synthesis". Nature. 207 (995): 417–8. doi:10.1038/207417a0. PMID 4957347.
  8. ↑ Campbell, E.A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., Darst, S.A. (2001). "Structural mechanism for rifampicin inhibition of bacterial RNA polymerase". Cell. 104 (6): 901–12. doi:10.1016/S0092-8674(01)00286-0. PMID 11290327.
  9. ↑ 9.0 9.1 Feklistov, A., Mekler, V., Jiang, Q., Westblade, L.F., Irschik, H., Jansen, R., Mustaev, A., Darst, S.A., Ebright, R.H. (2008). "Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center". Proc Natl Acad Sci USA. 105 (39): 14820–5. doi:10.1073/pnas.0802822105. PMC 2567451. PMID 18787125.
  10. ↑ Suarez J, Ranguelova K, Jarzecki AA; et al. (2009). "An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG)". The Journal of Biological Chemistry. 284 (11): 7017–29. doi:10.1074/jbc.M808106200. PMC 2652337. PMID 19139099. Unknown parameter |month= ignored (help)
  11. ↑ Timmins GS, Master S, Rusnak F, Deretic V (2004). "Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy. 48 (8): 3006–9. doi:10.1128/AAC.48.8.3006-3009.2004. PMC 478481. PMID 15273113. Unknown parameter |month= ignored (help)
  12. ↑ Singh R, Manjunatha U, Boshoff HI; et al. (2008). "PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release". Science. 322 (5906): 1392–5. doi:10.1126/science.1164571. PMC 2723733. PMID 19039139. Unknown parameter |month= ignored (help)
  13. ↑ PMID 19686043 (PMID 19686043)
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  14. ↑ Pharmacology, Harvey 4th edition. November 2009.
  15. ↑ Zhang Y, Mitchison D (2003). "The curious characteristics of pyrazinamide: a review". Int. J. Tuberc. Lung Dis. 7 (1): 6–21. PMID 12701830. Unknown parameter |month= ignored (help)
  16. ↑ Zimhony O, Cox JS, Welch JT, Vilchèze C, Jacobs WR (2000). "Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis" (abstract). Nature Medicine. 6 (9): 1043–47. doi:10.1038/79558. PMID 10973326.
  17. ↑ Boshoff HI, Mizrahi V, Barry CE (2002). "Effects of Pyrazinamide on Fatty Acid Synthesis by Whole Mycobacterial Cells and Purified Fatty Acid Synthase I". Journal of Bacteriology. 184 (8): 2167–72. doi:10.1128/JB.184.8.2167-2172.2002. PMC 134955. PMID 11914348.
  18. ↑ Zimhony O, Vilcheze C, Arai M, Welch J, Jacobs WR pi. Pyrazinoic acid and its n'Propyl Ester Inhibit Fatty Acid Synthase I in Replicating Tubercle Bacilli. Antimicrob Agents Chemother. 2007 51 752-754
  19. ↑ Ngo SC., Zimhony O, Chung WJ Sayahi, H, Jacobs WR. and JT. Welchpi. Inhibition of Isolated Mycobacterium tuberculosis Fatty Acid Synthase I by Pyrazinamide Analogs. Antimicrob Agents Chemother AntimicrobAgents Chemother. 2007; 1 2430-5
  20. ↑ 20.0 20.1 Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE; et al. (2011). "Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis". Science. 333 (6049): 1630–1632. doi:10.1126/science.1208813. PMID 21835980.
  21. ↑ Scorpio A, Zhang Y (1996). "Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus". Nature Medicine. 2 (6): 662–7. doi:10.1038/nm0696-662. PMID 8640557.
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