Pretomanid is an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

medication used for the treatment of

multi-drug-resistant tuberculosis Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are Antimicrobial resistance, resistant to treatment with at least two of the most powerful first-line Tuberculosis management, anti-TB m ...

affecting the

lungs The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...

. It is generally used together with

bedaquiline 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 mo ...

and

linezolid 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, va ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. The most common side effects include nerve damage,

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

, vomiting, headache,

low blood sugar Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

, diarrhea, and liver inflammation. It is in the

nitroimidazole Nitroimidazoles are the group of organic compound, organic compounds consisting of an imidazole ring with at least one nitro group substituent. The term also refers to the class of antibiotics that have nitroimidazole in their structures. These an ...

class of medications. Pretomanid was approved for medical use in the United States in August 2019, and in the European Union in July 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Pretomanid was developed by TB Alliance. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

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.

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 Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...

and a highly reactive metabolite. This metabolite attacks the synthesis enzyme ''DprE2'', which is important for the synthesis of cell wall

arabinogalactan Arabinogalactan, also known as galactoarabinan, larch arabinogalactan, and larch gum, is a biopolymer consisting of arabinose and galactose monosaccharides. Two classes of arabinogalactans are found in nature: plant arabinogalactan and microbial ...

, to which mycolic acid would be attached. This mechanism is shared with

delamanid 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. There are co ...

. Clinical isolates resistant to this drug tend to have mutations in the biosynthetic pathway for Coenzyme F₄₂₀.

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.

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). 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 Metronidazole, sold under the brand name Flagyl and Metrogyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vagino ...

. 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.

Society and culture

Legal status

The US

(FDA) approved pretomanid only in combination with

and

for treatment of a limited and specific population of adults with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary tuberculosis. Pretomanid was approved under the limited population pathway (LPAD pathway) for antibacterial and antifungal drugs. Pretomanid is only the third tuberculosis drug to receive approval from the FDA in more than 40 years. The FDA granted pretomanid

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

and

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

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

Names

Pretomanid is the international nonproprietary name, the generic name, and the nonproprietary name. Pretomanid is referred to as "Pa" in regimen abbreviations, such as BPaL. The "preto" part of the compound's name honors

Pretoria Pretoria ( ; ) is the Capital of South Africa, administrative capital of South Africa, serving as the seat of the Executive (government), executive branch of government, and as the host to all foreign embassies to the country. Pretoria strad ...

, 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

s or nitroimidazooxazines.

References

{{Authority control Anti-tuberculosis drugs Orphan drugs Prodrugs Trifluoromethyl ethers World Health Organization essential medicines