Identification

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Name
Pretomanid
Accession Number
DB05154
Type
Small Molecule
Groups
Approved
Description

Persistent forms of tuberculosis (TB) have proven to be a major cause of global morbidity and mortality and a cause for significant concern. Research in recent years has been geared toward the development of novel therapies that target persistent forms of this disease, which have shown resistance to standard therapy regimens.6 Pretomanid is an antimycobacterial agent that is administered with Bedaquiline and Linezolid to treat resistant forms of pulmonary TB. It was the first TB drug developed by a nonprofit organization, known as TB Alliance, and was granted FDA approval on August 14, 2019.10,13 Unlike other therapeutic regimens for the treatment of resistant TB, which may take 18 months or longer and may not be effective, the pretomanid-containing regimen allows for a more efficacious and shorter duration of treatment with fewer drugs.13

Structure
Thumb
Synonyms
  • Pretomanid
External IDs
PA 824 / PA-824 / PA824
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PretomanidTablet200 mg/1OralMylan Specialty Lp2019-08-14Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
2XOI31YC4N
CAS number
187235-37-6
Weight
Average: 359.2574
Monoisotopic: 359.072905124
Chemical Formula
C14H12F3N3O5
InChI Key
ZLHZLMOSPGACSZ-NSHDSACASA-N
InChI
InChI=1S/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1
IUPAC Name
(6S)-2-nitro-6-{[4-(trifluoromethoxy)phenyl]methoxy}-5H,6H,7H-imidazo[2,1-b][1,3]oxazine
SMILES
[O-][N+](=O)C1=CN2C[C@@H](COC2=N1)OCC1=CC=C(OC(F)(F)F)C=C1

Pharmacology

Indication

Pretomanid is indicated for adults in combination with bedaquiline and linezolid for the treatment of pulmonary forms of nonresponsive multidrug-resistant (MDR), extensively drug-resistant (XDR), and treatment-intolerant forms of pulmonary tuberculosis (TB).10

It is important to note that the following conditions are not approved indications for pretomanid therapy, according to the FDA10:

Drug-sensitive (DS) tuberculosis, latent tuberculosis caused by M.tuberculosis, extra-pulmonary tuberculosis caused by M.tuberculosis, and multidrug-resistant TB that is not treatment-intolerant or nonresponsive to conventional TB therapy.

Associated Conditions
Associated Therapies
Pharmacodynamics

Pretomanid kills the actively replicating bacteria causing tuberculosis, known as Mycobacterium tuberculosis, and shortens the duration of treatment in patients who suffer from resistant forms of pulmonary TB by killing dormant bacteria.4,5,7,10

In rodent models of tuberculosis infection, pretomanid administered in a regimen with bedaquiline and linezolid caused a significant reduction in pulmonary bacterial cell counts. A decrease in the frequency of TB relapses at 2 and 3 months after treatment was observed after the administration of this regimen, when compared to the administration of a 2-drug regimen.10 Successful outcomes have been recorded for patients with XDR and MDR following a clinical trial of the pretomanid regimen, demonstrating a 90% cure rate after 6 months.14

A note on cardiac QT prolongation, hepatotoxicity, and myelosuppression

This drug has the propensity to caused cardiac QT interval prolongation and significant hepatotoxicity, as well as myelosuppression. Caution must be observed during the administration of this drug.10,12

Mechanism of action

Pretomanid is a prodrug which is metabolically activated by a nitroreductase enzyme, known as Ddn, producing various active metabolites that are responsible for its other therapeutic actions, particularly the induction of nitric oxide. The nitroreductase enzyme which activates pretomanid is deazaflavin dependent and relies on reduced cofactor F420. Reduction of F420 occurs via the enzyme glucose-6-phosphate dehydrogenase.10 Reduction of pretomanid's imidazole ring at the C-3 position causes the formation of the metabolites, which include a des-nitro derivative. The formation of this derivative leads to increased levels of nitric oxide, leading to bactericidal activities under anaerobic conditions via its action as a bacterial respiratory poison.3,10 Bactericidal activity against anaerobes is reported to be associated with a shortened duration of antibiotic treatment.4

Pretomanid exerts aerobic bactericidal effects through its inhibitory actions on bacterial cell wall mycolic acid biosynthesis. This allows for the killing of actively replicating Mycobacterium tuberculosis bacteria, resulting in the treatment of active tuberculosis infection.4,10 The molecular mechanism of the above bactericidal effects is poorly understood at this time, but may involve effects exerted on various genes that affect the cell wall, including the fasI and fasII as well as the efpA and iniBAC operons. Other possible targets include the genes of the cyd operon. The clinical effects of the above target relations are unknown at this time.5

TargetActionsOrganism
UFatty acid synthetase
other/unknown
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
UUncharacterized MFS-type transporter EfpA
other/unknown
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
UNucleoid-associated protein Lsr2
other/unknown
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
UCyd operon, Mycobacterium tuberculosis
other/unknown
Mycobacterium tuberculosis
UEnoyl-[acyl-carrier-protein] reductase [NADH]
other/unknown
Mycobacterium tuberculosis
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

This drug is absorbed in the gastrointestinal tract. The steady-state Cmax of pretomanid was estimated to be 1.7 μg/mL after a single 200mg oral dose.10 In a separate pharmacokinetic modeling study, the Cmax of a 200mg dose was 1.1 μg/ml.2 Tmax in a study of healthy subjects in the fed or unfed state was achieved within 4 to 5 hours.10 The AUC in the same study was found to be about 28.1 μg•hr/mL in the fasted state and about 51.6 μg•hr/mL in the fed state, showing higher absorption when taken with high-calorie and high-fat food.10

Volume of distribution

A pharmacokinetic modeling study estimated the volume of distribution at 130 ± 5L.2 A pharmacokinetic study in healthy volunteers determined a volume of distribution of about 180 ± 51.3L in fasted state and 97.0 ± 17.2L in the fed state.10

Protein binding

The plasma protein binding of pretomanid is about 86.4%.10

Metabolism

Various reductive and oxidative pathways are responsible for pretomanid metabolism, with no single major metabolic pathway identified. According to in vitro studies, CYP3A4 is responsible for a 20% contribution to the metabolism of pretomanid.10

Route of elimination

Healthy adult male volunteers were administered a 1,100 mg oral dose of radiolabeled pretomanid in one pharmacokinetic study. An average of about 53% of the radioactive dose was found to be excreted in the urine. Approximately 38% was measured mainly as metabolites in the feces. A estimated 1% of the radiolabeled dose was measured as unchanged drug in the urine.10

Half life

The elimination half-life was determined to be 16.9-17.4 hours in a pharmacokinetic study of healthy subjects.10 An FDA briefing document reports a half-life of 18 hours.12

Clearance

The clearance of pretomanid in a pharmacokinetic simulation study has been estimated at 4.8 ± 0.2 liters/h.2 According to the FDA label, the clearance of a single 200 mg oral dose of pretomanid is estimated to be 7.6 liters/h in the fasted state, and 3.9 liters/h in the fed state.10

Toxicity

To this date, there is no documented experience with the treatment of a pretomanid overdose. The FDA label advises that general supportive measures are taken to manage an overdose, such as monitoring vital signs in addition to performing ECG testing for a prolonged QT interval in the case of an overdose.10

Affected organisms
  • Mycobacterium tuberculosis
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AprepitantThe serum concentration of Pretomanid can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Pretomanid can be increased when it is combined with Atazanavir.
BarnidipineThe serum concentration of Pretomanid can be increased when it is combined with Barnidipine.
BenidipineThe serum concentration of Pretomanid can be increased when it is combined with Benidipine.
BoceprevirThe serum concentration of Pretomanid can be increased when it is combined with Boceprevir.
ClarithromycinThe serum concentration of Pretomanid can be increased when it is combined with Clarithromycin.
ClozapineThe serum concentration of Pretomanid can be increased when it is combined with Clozapine.
CobicistatThe serum concentration of Pretomanid can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Pretomanid can be increased when it is combined with Conivaptan.
CrizotinibThe serum concentration of Pretomanid can be increased when it is combined with Crizotinib.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

Synthesis Reference

Thompson AM, Bonnet M, Lee HH, et al. Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. ACS Med Chem Lett. 2017;8(12):1275–1280. Published 2017 Nov 13. doi:10.1021/acsmedchemlett.7b00356

General References
  1. Xu J, Li SY, Almeida DV, Tasneen R, Barnes-Boyle K, Converse PJ, Upton AM, Mdluli K, Fotouhi N, Nuermberger EL: Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.00021-19. doi: 10.1128/AAC.00021-19. Print 2019 May. [PubMed:30833432]
  2. Lyons MA: Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: AAC.02359-17. doi: 10.1128/AAC.02359-17. Print 2018 Jul. [PubMed:29661865]
  3. Baptista R, Fazakerley DM, Beckmann M, Baillie L, Mur LAJ: Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824). Sci Rep. 2018 Mar 23;8(1):5084. doi: 10.1038/s41598-018-23110-1. [PubMed:29572459]
  4. Thompson AM, Bonnet M, Lee HH, Franzblau SG, Wan B, Wong GS, Cooper CB, Denny WA: Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. ACS Med Chem Lett. 2017 Nov 13;8(12):1275-1280. doi: 10.1021/acsmedchemlett.7b00356. eCollection 2017 Dec 14. [PubMed:29259747]
  5. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]
  6. Sacchettini JC, Rubin EJ, Freundlich JS: Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nat Rev Microbiol. 2008 Jan;6(1):41-52. doi: 10.1038/nrmicro1816. [PubMed:18079742]
  7. Cano-Muniz S, Anthony R, Niemann S, Alffenaar JC: New Approaches and Therapeutic Options for Mycobacterium tuberculosis in a Dormant State. Clin Microbiol Rev. 2017 Nov 29;31(1). pii: 31/1/e00060-17. doi: 10.1128/CMR.00060-17. Print 2018 Jan. [PubMed:29187395]
  8. Kwon YS: Clinical Implications of New Drugs and Regimens for the Treatment of Drug-resistant Tuberculosis. Chonnam Med J. 2017 May;53(2):103-109. doi: 10.4068/cmj.2017.53.2.103. Epub 2017 May 25. [PubMed:28584788]
  9. Bahuguna A, Rawat DS: An overview of new antitubercular drugs, drug candidates, and their targets. Med Res Rev. 2019 Jun 28. doi: 10.1002/med.21602. [PubMed:31254295]
  10. Pretomanid FDA label, August 2019 [Link]
  11. MSDS, Pretomanid [Link]
  12. Pretomanid briefing document, FDA [Link]
  13. TB Alliance [Link]
  14. TB Alliance presentation slides [Link]
External Links
PubChem Compound
456199
PubChem Substance
175426953
ChemSpider
401693
BindingDB
50363237
ChEMBL
CHEMBL227875
Wikipedia
Pretomanid

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentTuberculosis Infection6
1RecruitingTreatmentImpaired Renal Function / Tuberculosis Infection1
1RecruitingTreatmentTuberculosis Infection1
2CompletedTreatmentPulmonary Tuberculosis (TB)5
2CompletedTreatmentTuberculosis Infection1
2RecruitingTreatmentPulmonary Tuberculosis (TB)1
2, 3Not Yet RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Multi-Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB)1
2, 3Not Yet RecruitingTreatmentTuberculosis, Multidrug Resistant1
2, 3RecruitingTreatmentDrug-resistant Tuberculosis / Extensively Drug Resistant Tuberculosis / Multi-Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB) / Tuberculosis Infection / Tuberculosis, Multidrug Resistant1
2, 3RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB) / Tuberculosis, Multidrug Resistant1
3Active Not RecruitingTreatmentPulmonary Tuberculosis (TB)1
3CompletedTreatmentPulmonary Multi-Drug Resistant Tuberculosis (MDR-TB) / Tuberculosis, Pulmonary, Drug Sensitive1
3RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Multi-Drug Resistant Tuberculosis / Pre-XDR-TB / Pulmonary Tuberculosis (TB) / Tuberculosis Infection / Tuberculosis, Multidrug Resistant1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral200 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)462.3±55.0http://www.chemspider.com/Chemical-Structure.401693.html
water solubility<1 mg/mLhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139342/
logP2.75https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139342/
Caco2 permeability27.6https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139342/
pKa7.0https://www.researchgate.net/publication/310833979_Simultaneous_HPLC_assay_for_pretomanid_PA-824_moxifloxacin_and_pyrazinamide_in_an_inhaler_formulation_for_drug-resistant_tuberculosis
Predicted Properties
PropertyValueSource
Water Solubility0.0117 mg/mLALOGPS
logP2.8ALOGPS
logP4.14ChemAxon
logS-4.5ALOGPS
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area91.33 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity73.91 m3·mol-1ChemAxon
Polarizability30.26 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9907
Blood Brain Barrier+0.9623
Caco-2 permeable-0.5858
P-glycoprotein substrateNon-substrate0.5647
P-glycoprotein inhibitor INon-inhibitor0.5203
P-glycoprotein inhibitor IIInhibitor0.6073
Renal organic cation transporterNon-inhibitor0.7711
CYP450 2C9 substrateNon-substrate0.8673
CYP450 2D6 substrateNon-substrate0.807
CYP450 3A4 substrateSubstrate0.5977
CYP450 1A2 substrateInhibitor0.5382
CYP450 2C9 inhibitorNon-inhibitor0.5545
CYP450 2D6 inhibitorNon-inhibitor0.824
CYP450 2C19 inhibitorInhibitor0.5471
CYP450 3A4 inhibitorNon-inhibitor0.5201
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7631
Ames testAMES toxic0.6851
CarcinogenicityNon-carcinogens0.7434
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6368 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.724
hERG inhibition (predictor II)Non-inhibitor0.5098
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzylethers. These are aromatic ethers with the general formula ROCR' (R = alkyl, aryl; R'=benzene).
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzylethers
Direct Parent
Benzylethers
Alternative Parents
Phenoxy compounds / Phenol ethers / Nitroimidazoles / Nitroaromatic compounds / Alkyl aryl ethers / N-substituted imidazoles / Imidolactams / Heteroaromatic compounds / Trihalomethanes / Propargyl-type 1,3-dipolar organic compounds
show 10 more
Substituents
Benzylether / Phenoxy compound / Nitroaromatic compound / Nitroimidazole / Phenol ether / Alkyl aryl ether / N-substituted imidazole / Imidolactam / Azole / Imidazole
show 26 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Pharmacological action
Unknown
Actions
Other/unknown
Curator comments
Possible target, unconfirmed.
General Function
Not Available
Specific Function
Enoyl-[acyl-carrier-protein] reductase (nadh) activity
Gene Name
fas
Uniprot ID
P95029
Uniprot Name
Probable fatty acid synthase Fas (Fatty acid synthetase)
Molecular Weight
326251.13 Da
References
  1. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]
Kind
Protein
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Pharmacological action
Unknown
Actions
Other/unknown
Curator comments
Possible target, unconfirmed.
General Function
Not Available
Specific Function
Not Available
Gene Name
efpA
Uniprot ID
P9WJY5
Uniprot Name
Uncharacterized MFS-type transporter EfpA
Molecular Weight
55578.955 Da
References
  1. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]
Kind
Protein
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Pharmacological action
Unknown
Actions
Other/unknown
Curator comments
Possible target, unconfirmed.
General Function
DNA-bridging protein that has both architectural and regulatory roles (PubMed:18187505). Influences the organization of chromatin and gene expression by binding non-specifically to DNA, with a preference for AT-rich sequences, and bridging distant DNA segments (PubMed:20133735). Binds in the minor groove of AT-rich DNA (PubMed:21673140). Represses expression of multiple genes involved in a broad range of cellular processes, including major virulence factors or antibiotic-induced genes, such as iniBAC or efpA (PubMed:17590082), and genes important for adaptation of changing O(2) levels (PubMed:24895305). May also activate expression of some gene (PubMed:24895305). May coordinate global gene regulation and virulence (PubMed:20133735). Also protects mycobacteria against reactive oxygen intermediates during macrophage infection by acting as a physical barrier to DNA degradation (PubMed:19237572); the physical protection has been questioned (PubMed:24895305). A strain overexpressing this protein consumes O(2) more slowly than wild-type (PubMed:24895305).
Specific Function
Dna binding
Gene Name
lsr2
Uniprot ID
P9WIP7
Uniprot Name
Nucleoid-associated protein Lsr2
Molecular Weight
12098.335 Da
References
  1. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]
Kind
Protein group
Organism
Mycobacterium tuberculosis
Pharmacological action
Unknown
Actions
Other/unknown
Curator comments
Possible target, unconfirmed.
General Function
Not Available
Specific Function
Atp binding

Components:
References
  1. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]
Kind
Protein
Organism
Mycobacterium tuberculosis
Pharmacological action
Unknown
Actions
Other/unknown
Curator comments
Possible target, unconfirmed.
General Function
Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, which is involved in the biosynthesis of mycolic acids, a major component of mycobacterial cell walls (PubMed:25227413). Catalyzes the NADH-dependent reduction of the double bond of 2-trans-enoyl-[acyl-carrier protein], an essential step in the fatty acid elongation cycle of the FAS-II pathway (PubMed:7599116). Shows preference for long-chain fatty acyl thioester substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative substrates (PubMed:7599116). The mycobacterial FAS-II system utilizes the products of the FAS-I system as primers to extend fatty acyl chain lengths up to C56, forming the meromycolate chain that serves as the precursor for final mycolic acids (PubMed:25227413).
Specific Function
Enoyl-[acyl-carrier-protein] reductase (nadh) activity
Gene Name
inhA
Uniprot ID
P9WGR1
Uniprot Name
Enoyl-[acyl-carrier-protein] reductase [NADH]
Molecular Weight
28527.55 Da
References
  1. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Pretomanid briefing document, FDA [Link]
  2. Pretomanid FDA label, August 2019 [Link]
Kind
Protein
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Pharmacological action
Unknown
Actions
Substrate
General Function
Involved in a F420-dependent anti-oxidant mechanism that protects M.tuberculosis against oxidative stress and bactericidal agents. Catalyzes the F420H(2)-dependent two-electron reduction of quinones to dihydroquinones, thereby preventing the formation of cytotoxic semiquinones obtained by the one-electron reduction pathway (PubMed:23240649). In vitro, catalyzes the reduction of both benzoquinone and naphthoquinone analogs; since menaquinone is the sole quinone electron carrier in the respiratory chain in M.tuberculosis, the physiological electron acceptor for Fqr-mediated F420H(2) oxidation is therefore likely to be the endogenous menaquinone found in the membrane fraction of M.tuberculosis (PubMed:23240649). Is able to use F420 species with two and five glutamate residues in its polyglutamate tail (PubMed:22023140). Cannot use NADH or NADPH instead of F420H(2) as the electron donor (PubMed:23240649).
Specific Function
Coenzyme f420 binding
Gene Name
ddn
Uniprot ID
P9WP15
Uniprot Name
Deazaflavin-dependent nitroreductase
Molecular Weight
17370.87 Da
References
  1. Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926. [PubMed:19641733]
  2. Thompson AM, Bonnet M, Lee HH, Franzblau SG, Wan B, Wong GS, Cooper CB, Denny WA: Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. ACS Med Chem Lett. 2017 Nov 13;8(12):1275-1280. doi: 10.1021/acsmedchemlett.7b00356. eCollection 2017 Dec 14. [PubMed:29259747]
  3. Pretomanid FDA label, August 2019 [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Pretomanid FDA label, August 2019 [Link]
  2. Pretomanid briefing document, FDA [Link]

Drug created on October 21, 2007 16:23 / Updated on September 02, 2019 18:09