Solithromycin (trade name Solithera) is a

ketolide Ketolides are antibiotics belonging to the macrolide group. Ketolides are derived from erythromycin by substituting the cladinose sugar with a keto-group and attaching a cyclic carbamate group in the lactone ring. These modifications give keto ...

antibiotic undergoing clinical development for the treatment of

community-acquired pneumonia Community-acquired pneumonia (CAP) refers to pneumonia (any of several lung diseases) contracted by a person outside of the healthcare system. In contrast, hospital-acquired pneumonia (HAP) is seen in patients who have recently visited a hospital ...

and other infections. Solithromycin exhibits excellent ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' activity against a broad spectrum of

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

respiratory tract

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

s, including macrolide-resistant strains. Solithromycin has activity against most common respiratory Gram-positive and fastidious Gram-negative pathogens, and is being evaluated for its utility in treating

gonorrhea Gonorrhea, colloquially known as the clap, is a sexually transmitted infection (STI) caused by the bacterium ''Neisseria gonorrhoeae''. Infection may involve the genitals, mouth, or rectum. Infected men may experience pain or burning with u ...

Pre-clinical studies

An ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' pre-clinical study performed by Jeffrey Keelan done in sheep may provide a prophylactic approach for intrauterine infections during pregnancy. This study was carried out by administering solithromycin to pregnant sheep, resulting in effective concentrations greater than 30 ng/ml in the fetal plasma, maternal plasma and amniotic fluid. A single maternal dose maintained these concentrations for over 12 hours.

Clinical trials

*May 2011: solithromycin is in a Phase 2 clinical trial for serious community-acquired bacterial pneumonia and in a Phase 1 clinical trial with an intravenous formulation. *September 2011: solithromycin demonstrated comparable efficacy to levofloxacin with reduced adverse events in Phase 2 trial in people with community-acquired pneumonia *January 2015: in a Phase 3 clinical trial for community-acquired bacterial pneumonia, solithromycin administered orally demonstrated statistical non-inferiority to the fluoroquinolone

moxifloxacin Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop. Common side effects in ...

. *July 2015: patient enrollment for the second Phase 3 clinical trial (Solitaire IV) for community-acquired bacterial pneumonia was completed with results expected in Q4 2015. *Oct 2015: IV to oral solithromycin demonstrated statistical non-inferiority to IV to oral moxifloxacin in adults with community-acquired bacterial pneumonia. *July 2016: Cempra announced FDA acceptance of IV and oral formulations of Solithera (solithromycin) new drug applications for the treatment of community-acquired bacterial pneumonia.

Structure

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

studies have shown solithromycin, the first fluoroketolide in clinical development, has a third region of interactions with the bacterial ribosome, as compared with two binding sites for other

s. The only previously marketed

telithromycin Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant safety concerns, the US Food and Drug ...

, suffers from rare but serious

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s. Recent studies have shown this to be likely due to the presence of the

pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...

imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-a ...

group of the telithromycin side chain acting as an antagonist towards various

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

s. Solithromycin differs from telithromycin because the side chain does not significantly antagonize nicotinic acetylcholine receptors. Instead of the pyridine-imidazole group used on telithromycin, this molecule has a triazole-phenylamine moiety.

Mechanism of action

Solithromycin inhibits bacterial translation by binding to the

23S ribosomal RNA The 23S rRNA is a 2,904 nucleotide long (in '' E. coli'') component of the large subunit (50S) of the bacterial/archean ribosome and makes up the peptidyl transferase center (PTC). The 23S rRNA is divided into six secondary structural domains ...

, preventing the offending bacteria from synthesizing proteins.

Side effects

During a clinical study some patients presented with elevated liver enzyme which may or may not be indicative of

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

. This prompted the FDA Antimicrobial Drugs Advisory Committee to vote that the risk to the liver has not been adequately characterized and that further studies need to be conducted. To this extent, the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

requests a 9,000 patient safety trial as well as restricting the drug.

Development

In 2008, investigational new drug applications for solithromycin capsules and an intravenous formulation were submitted. From studies of pharmacokinetics, safety, and efficacy several issues were found. There is variable absorption which can result in subtherapeutic drug concentrations and even therapy failure. Additionally, there are significant drug-drug interactions affecting solithromycin concentrations as well the concentrations of the offending drugs. There is also a narrow therapeutic margin which can make this drug challenging to dose.

Commercial aspects

Cempra's general plan is to develop solithromycin develop products through late stage clinical trials and sell them to their hospital based sales force or through partnerships, which would need negotiations with larger pharmaceutical companies. There are several manufacturing plants used such as Wockhardt Limited and Hospira Incorporated manufacturing facilities as well as Uquifa Laboratories, an alternative GMP facility.

Intellectual property

Due to the fact that bringing new products to the market takes a significant investment of time and money, companies place considerable importance on patent protection for new products. Solithromycin is a new chemical entity from the

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

library of compounds that were licensed by Optimer. It is covered by a series of patents and patent applications which claim the composition of matter of solithromycin. There are also patents surrounding the synthesis and purification of this substance. For example, patent EP3190122 A1 presents a novel, efficient route of synthesis that bypasses the need for chromatographic purification which saves time.