Pretomanid

Last updated

Pretomanid
Pretomanid.svg
Clinical data
Trade names Dovprela
Other namesPA-824
AHFS/Drugs.com Monograph
MedlinePlus a619056
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b] [1,3]oxazine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H12F3N3O5
Molar mass 359.261 g·mol−1
3D model (JSmol)
  • C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F
  • 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 X mark.svgN
  • Key:ZLHZLMOSPGACSZ-NSHDSACASA-N X mark.svgN

Pretomanid is an antibiotic medication used for the treatment of multi-drug-resistant tuberculosis affecting the lungs. [4] [5] It is generally used together with bedaquiline and linezolid. [4] It is taken by mouth. [4]

Contents

The most common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation. [4] It is in the nitroimidazole class of medications. [6]

Pretomanid was approved for medical use in the United States in August 2019, [4] [7] and in the European Union in July 2020. [2] Pretomanid was developed by TB Alliance. [8] [4] [9] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication. [10] It is on the World Health Organization's List of Essential Medicines. [11]

Medical uses

Pretomanid is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant, or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. [2] [1]

Mechanism of action

Pretomanid is activated in the mycobacterium by deazaflavin-dependent nitroreductase (Ddn), an enzyme which uses dihydro-F420 (reduced form), into nitric oxide and a highly reactive metabolite. This metabolite attacks the synthesis enzyme DprE2, which is important for the synthesis of cell wall arabinogalactan, to which mycolic acid would be attached. This mechanism is shared with delamanid. Clinical isolates resistant to this drug tend to have mutations in the biosynthetic pathway for Coenzyme F420. [12]

History

Development of this compound was initiated because of the urgent need for new antibacterial drugs effective against resistant strains of tuberculosis. Also, current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, creating a need for drugs effective against persisting or latent bacterial infections as often occur in patients with tuberculosis. [13]

Discovery and pre-clinical development

Pretomanid was first identified in 2000, in a series of 100 nitroimidazopyran derivatives synthesized and tested for antitubercular activity, by PathoGenesis (now a subsidiary of Novartis). [14] Importantly, pretomanid has activity against static M. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drug metronidazole. Pretomanid requires metabolic activation by Mycobacterium for antibacterial activity. Pretomanid was not the most potent compound in the series against cultures of M. tuberculosis, but it was the most active in infected mice after oral administration. Oral pretomanid was active against tuberculosis in mice and guinea pigs at safely tolerated dosages for up to 28 days. [13]

Society and culture

The US Food and Drug Administration (FDA) approved pretomanid only in combination with bedaquiline and linezolid for treatment of a limited and specific population of adults with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary tuberculosis. [4] [7] Pretomanid was approved under the limited population pathway (LPAD pathway) for antibacterial and antifungal drugs. [4] Pretomanid is only the third tuberculosis drug to receive approval from the FDA in more than 40 years. [4] [9]

The FDA granted pretomanid priority review and orphan drug designations. [4] The FDA granted The Global Alliance for TB Drug Development (TB Alliance) the approval of pretomanid and a tropical disease priority review voucher. [4]

Names

Pretomanid is the international nonproprietary name, the generic name, and the nonproprietary name. [15] [16] Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" part of the compound's name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drug's development took place, while the "-manid" stem designates compounds with similar chemical structures. This class of drug is variously referred to as nitroimidazoles or nitroimidazooxazines.

Related Research Articles

<span class="mw-page-title-main">Linezolid</span> Antibiotic medication

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<span class="mw-page-title-main">Rifabutin</span> Chemical compound

Rifabutin (Rfb) is an antibiotic used to treat tuberculosis and prevent and treat Mycobacterium avium complex. It is typically only used in those who cannot tolerate rifampin such as people with HIV/AIDS on antiretrovirals. For active tuberculosis it is used with other antimycobacterial medications. For latent tuberculosis it may be used by itself when the exposure was with drug-resistant TB.

<span class="mw-page-title-main">Rifapentine</span> Chemical compound

Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.

TB Alliance is a not-for-profit product development partnership (PDP) dedicated to the discovery and development of new, faster-acting and affordable tuberculosis (TB) medicines. Since its inception in 2000, TB Alliance has worked to grow the field of available treatments for TB and now manages the largest pipeline of new TB drugs in history. It was founded in Cape Town, South Africa, and has since expanded. It is headquartered in New York City and has a regional office in Pretoria.

<span class="mw-page-title-main">Ethionamide</span> Chemical compound

Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.

<span class="mw-page-title-main">Extensively drug-resistant tuberculosis</span> Tuberculosis that is resistant to the most effective drugs

Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to some of the most effective anti-TB drugs. XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

<span class="mw-page-title-main">Bedaquiline</span> Medication used to treat tuberculosis

Bedaquiline, sold under the brand name Sirturo, is a medication used for the treatment of active tuberculosis. Specifically, it is used to treat multi-drug-resistant tuberculosis along with other medications for tuberculosis. It is taken by mouth.

<span class="mw-page-title-main">Ceftobiprole</span> Chemical compound

Ceftobiprole, sold under the brand name Zevtera among others, is a fifth-generation cephalosporin antibacterial used for the treatment of hospital-acquired pneumonia and community-acquired pneumonia. It is marketed by Basilea Pharmaceutica under the brand names Zevtera and Mabelio. Like other cephalosporins, ceftobiprole exerts its antibacterial activity by binding to important penicillin-binding proteins and inhibiting their transpeptidase activity which is essential for the synthesis of bacterial cell walls. Ceftobiprole has high affinity for penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus strains and retains its activity against strains that express divergent mecA gene homologues. Ceftobiprole also binds to penicillin-binding protein 2b in Streptococcus pneumoniae (penicillin-intermediate), to penicillin-binding protein 2x in Streptococcus pneumoniae (penicillin-resistant), and to penicillin-binding protein 5 in Enterococcus faecalis.

Coenzyme F<sub>420</sub> Chemical compound

Coenzyme F420 is a family of coenzymes involved in redox reactions in a number of bacteria and archaea. It is derived from coenzyme FO (7,8-didemethyl-8-hydroxy-5-deazariboflavin) and differs by having a oligoglutamyl tail attached via a 2-phospho-L-lactate bridge. F420 is so named because it is a flavin derivative with an absorption maximum at 420 nm.

<span class="mw-page-title-main">Tedizolid</span> Oxazolidinone-class antibiotic

Tedizolid, sold under the brand name Sivextro is an oxazolidinone-class antibiotic. Tedizolid phosphate is a phosphate ester prodrug of the active compound tedizolid. It was developed by Cubist Pharmaceuticals, following acquisition of Trius Therapeutics, and is marketed for the treatment of acute bacterial skin and skin structure infections.

Delamanid is sold under the brand name Deltyba, is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

<span class="mw-page-title-main">Omadacycline</span> Chemical compound

Omadacycline, sold under the brand name Nuzyra, is a broad spectrum antibiotic medication belonging to the aminomethylcycline subclass of tetracycline antibiotics. In the United States, it was approved in October 2018, for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

<span class="mw-page-title-main">Mirvetuximab soravtansine</span> Pharmaceutical drug

Mirvetuximab soravtansine, sold under the brand name Elahere, is a medication used as a treatment for epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Mirvetuximab soravtansine is a folate receptor alpha directed antibody and microtubule inhibitor conjugate.

<span class="mw-page-title-main">Lefamulin</span> Chemical compound

Lefamulin, sold under the brand name Xenleta, is an antibiotic medication used it to treat adults with community-acquired bacterial pneumonia. It is taken by mouth or by injection into a vein.

<span class="mw-page-title-main">Anil Koul</span> Indian scientist (born 1972)

Anil Koul is a scientist and former Director of the CSIR-Institute of Microbial Technology (IMTECH), a premier biomedical and biotechnology research institution under Council of Scientific and Industrial Research (CSIR) under Ministry of Science and Technology, Govt. of India.

Phumeza Tisile is a healthcare activist from South Africa who advocates for making tuberculosis medication inexpensive and widely available. Tisile survived extensively drug-resistant tuberculosis (XDR-TB), enduring three years and 8 months of treatment. Tisile's initial misdiagnoses led to months of incorrect treatment, which caused her to become deaf. As an activist, Tisile advocates for improved access to tuberculosis (TB) diagnosis and treatment, improved counseling for patients, research into better treatments, and elimination of TB stigma.

References

  1. 1 2 "Pretomanid tablet". DailyMed. 15 September 2019. Retrieved 25 September 2020.
  2. 1 2 3 "Dovprela (previously Pretomanid FGK) EPAR". European Medicines Agency (EMA). 24 March 2020. Retrieved 25 September 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ↑ "Dovprela Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  4. 1 2 3 4 5 6 7 8 9 10 11 "FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs". U.S. Food and Drug Administration (FDA) (Press release). 14 August 2019. Retrieved 28 August 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. ↑ "Drug Trials Snapshots: Pretomanid". U.S. Food and Drug Administration (FDA). 14 August 2019. Retrieved 17 March 2020.
  6. ↑ "Our Pipeline". TB Alliance. 19 July 2015. Retrieved 18 April 2019.
  7. 1 2 "Drug Approval Package: Pretomanid". U.S. Food and Drug Administration (FDA). 12 September 2019. Retrieved 25 September 2020.
  8. ↑ "TB Medicine Pretomanid Enters Regulatory Review Process in the United States". TB Alliance . 8 March 2019. Retrieved 18 April 2019.
  9. 1 2 Abutaleb Y (14 August 2019). "New antibiotic approved for drug-resistant tuberculosis". The Washington Post .
  10. ↑ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Retrieved 15 September 2020.
  11. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  12. ↑ Abrahams KA, Batt SM, Gurcha SS, Veerapen N, Bashiri G, Besra GS (June 2023). "DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid". Nature Communications. 14 (1): 3828. Bibcode:2023NatCo..14.3828A. doi: 10.1038/s41467-023-39300-z . PMC   10307805 . PMID   37380634.
  13. 1 2 Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. (June 2005). "Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models". Antimicrobial Agents and Chemotherapy. 49 (6): 2294–2301. doi:10.1128/AAC.49.6.2294-2301.2005. PMC   1140539 . PMID   15917524.
  14. ↑ Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. (June 2000). "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis". Nature. 405 (6789): 962–966. Bibcode:2000Natur.405..962S. doi:10.1038/35016103. PMID   10879539. S2CID   4428584.
  15. ↑ World Health Organization (2014). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 72". WHO Drug Information. 28 (3). hdl: 10665/331112 .
  16. ↑ "PA-824 has a New Generic Name: Pretomanid". TB Alliance. 20 October 2014. Retrieved 18 April 2019.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.