Solithromycin

Last updated
Solithromycin
Solithromycin.svg
Clinical data
Trade names Solithera
Other namesCEM-101; OP-1068
Routes of
administration 		Oral, intravenous
ATC code
Legal status
Legal status
  • Under FDA and EMA review for approval
Identifiers
  • (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-1-[4-[4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl]butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-2H-Oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone
CAS Number
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C43H65FN6O10
Molar mass 845.023 g·mol−1
3D model (JSmol)
  • CC[C@@H]1[C@@]2([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H](C(=O)[C@](C(=O)O1)(C)F)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)N(C(=O)O2)CCCCn4cc(nn4)c5cccc(c5)N)C
  • InChI=1S/C43H65FN6O10/c1-12-32-43(8)35(50(40(55)60-43)19-14-13-18-49-23-30(46-47-49)28-16-15-17-29(45)21-28)26(4)33(51)24(2)22-41(6,56-11)37(27(5)36(53)42(7,44)39(54)58-32)59-38-34(52)31(48(9)10)20-25(3)57-38/h15-17,21,23-27,31-32,34-35,37-38,52H,12-14,18-20,22,45H2,1-11H3/t24-,25-,26+,27+,31+,32-,34-,35-,37-,38+,41-,42+,43-/m1/s1 X mark.svgN
  • Key:IXXFZUPTQVDPPK-ZAWHAJPISA-N X mark.svgN
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Solithromycin (trade name Solithera) is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia [1] and other infections. [2]

Contents

Solithromycin exhibits excellent in vitro activity against a broad spectrum of Gram-positive respiratory tract pathogens, [3] [4] including macrolide-resistant strains. [5] Solithromycin has activity against most common respiratory Gram-positive and fastidious Gram-negative pathogens, [6] [7] and is being evaluated for its utility in treating gonorrhea.

Pre-clinical studies

An in vivo 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. [8]

Clinical trials

Structure

X-ray crystallography studies have shown solithromycin, the first fluoroketolide in clinical development, has a third region of interactions with the bacterial ribosome, [15] as compared with two binding sites for other ketolides.

The only previously marketed ketolide, telithromycin, suffers from rare but serious side effects. Recent studies [16] have shown this to be likely due to the presence of the pyridine-imidazole group of the telithromycin side chain acting as an antagonist towards various nicotinic acetylcholine receptors. Solithromycin differs from telithromycin because the side chain does not significantly antagonize nicotinic acetylcholine receptors. [17] Instead of the pyridine-imidazole group used on telithromycin, this molecule has a triazole-phenylamine moiety.[ citation needed ]

Mechanism of action

Solithromycin inhibits bacterial translation by binding to the 23S ribosomal RNA, preventing the offending bacteria from synthesizing proteins. [18]

Side effects

During a clinical study some patients presented with elevated liver enzyme which may or may not be indicative of hepatotoxicity. 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 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. [19]

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. [20] There are several manufacturing plants used such as Wockhardt Limited and Hospira Incorporated manufacturing facilities as well as Uquifa Laboratories, an alternative GMP facility. [21]

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 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. [22] 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. [23]

Related Research Articles

<span class="mw-page-title-main">Macrolide</span> Class of natural products

Macrolides are a class of mostly natural products with 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. Macrolides belong to the polyketide class of natural products. Some macrolides have antibiotic or antifungal activity and are used as pharmaceutical drugs. Rapamycin is also a macrolide and was originally developed as an antifungal, but is now used as an immunosuppressant drug and is being investigated as a potential longevity therapeutic.

<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">Clindamycin</span> Antibiotic

Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.

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

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 Administration sharply curtailed the approved uses of the drug in early 2007.

<span class="mw-page-title-main">Fusidic acid</span> Antibiotic

Fusidic acid, sold under the brand names Fucidin among others, is an antibiotic that is often used topically in creams or ointments and eyedrops but may also be given systemically as tablets or injections.
As of October 2008, the global problem of advancing antimicrobial resistance has led to a renewed interest in its use.

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

Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

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

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

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

Iclaprim is an antibiotic drug candidate that is active against Gram positive organisms. It is administered intravenously.

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

Tedizolid, 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.

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

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

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

Nemonoxacin is a non-fluorinated quinolone antibiotic undergoing clinical trials. It has the same mechanism of action as fluouroquinolones; it inhibits DNA gyrase, preventing DNA synthesis, gene duplication, and cell division. At the end of 2016, it had reached market in Taiwan, Russia, the Commonwealth Independent States, Turkey, mainland China, and Latin America under the brand name Taigexyn. Nemonoxacin has completed phase 2 trials in the US and has moved on to phase 3 trials. The U.S. Food and Drug Administration (FDA) has granted nemonoxacin qualified infectious disease product (QIDP) and fast track designations for community-acquired bacterial pneumonia (CAP) and acute bacterial skin and skin-structure infections (ABSSSI).

<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">Eravacycline</span> Chemical compound

Eravacycline is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA and is currently available in USA.

<span class="mw-page-title-main">Ceftolozane/tazobactam</span> Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

<span class="mw-page-title-main">Sarecycline</span> Antibiotic medication used to treat acne

Sarecycline, sold under the brand name Seysara, is a narrow-spectrum tetracycline-derived antibiotic medication. It is specifically designed for the treatment of acne, and was approved by the FDA in October 2018 for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older. Two randomized and well-controlled clinical trials reported efficacy data on both facial and truncal acne. Efficacy was assessed in a total of 2002 subjects 9 years of age and older. Unlike other tetracycline-class antibiotics, sarecycline has a long C7 moiety that extends into and directly interact with the bacterial messenger RNA (mRNA). The spectrum of activity is limited to clinically relevant Gram-positive bacteria, mainly Cutibacterium acnes, with little or no activity against Gram-negative bacterial microflora commonly found in the human gastrointestinal tract.

<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.

Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.

Imipenem/cilastatin/relebactam, sold under the brand name Recarbrio, is a fixed-dose combination medication used as an antibiotic. In 2019, it was approved for use in the United States for the treatment of complicated urinary tract and complicated intra-abdominal infections. It is administered via intravenous injection.

References

  1. ↑ Reinert RR (June 2004). "Clinical efficacy of ketolides in the treatment of respiratory tract infections". The Journal of Antimicrobial Chemotherapy. 53 (6): 918–927. doi: 10.1093/jac/dkh169 . PMID   15117934.
  2. ↑ "Solithromycin". Cempra. Archived from the original on 18 March 2012.
  3. ↑ Woosley LN, Castanheira M, Jones RN (May 2010). "CEM-101 activity against Gram-positive organisms". Antimicrobial Agents and Chemotherapy. 54 (5): 2182–2187. doi:10.1128/AAC.01662-09. PMC   2863667 . PMID   20176910.
  4. ↑ Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN (June 2010). "Antimicrobial characterisation of CEM-101 activity against respiratory tract pathogens, including multidrug-resistant pneumococcal serogroup 19A isolates". International Journal of Antimicrobial Agents. 35 (6): 537–543. doi:10.1016/j.ijantimicag.2010.01.026. PMID   20211548.
  5. ↑ McGhee P, Clark C, Kosowska-Shick KM, Nagai K, Dewasse B, Beachel L, Appelbaum PC (January 2010). "In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms". Antimicrobial Agents and Chemotherapy. 54 (1): 230–238. doi:10.1128/AAC.01123-09. PMC   2798494 . PMID   19884376.
  6. ↑ Putnam SD, Castanheira M, Moet GJ, Farrell DJ, Jones RN (April 2010). "CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria". Diagnostic Microbiology and Infectious Disease. 66 (4): 393–401. doi:10.1016/j.diagmicrobio.2009.10.013. PMID   20022192.
  7. ↑ Putnam SD, Sader HS, Farrell DJ, Biedenbach DJ, Castanheira M (January 2011). "Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci". International Journal of Antimicrobial Agents. 37 (1): 39–45. doi:10.1016/j.ijantimicag.2010.08.021. PMID   21075602.
  8. ↑ Keelan JA, Kemp MW, Payne MS, Johnson D, Stock SJ, Saito M, et al. (4 November 2013). "Maternal administration of solithromycin, a new, potent, broad-spectrum fluoroketolide antibiotic, achieves fetal and intra-amniotic antimicrobial protection in a pregnant sheep model". Antimicrobial Agents and Chemotherapy. 58 (1): 447–454. doi:10.1128/AAC.01743-13. PMC   3910757 . PMID   24189250.
  9. ↑ "Intravenous (IV) Administration of Cempra Pharmaceutical's Solithromycin (CEM-101) Demonstrates Excellent Systemic Tolerability in a Phase 1 Clinical Trial". 7 May 2011.
  10. ↑ "Cempra antibiotic compound as effective, safer than levofloxacin". 15 Sep 2011.
  11. ↑ http://investor.cempra.com/releasedetail.cfm?ReleaseID=889300. 4 Jan 2015 Archived 25 March 2015 at the Wayback Machine
  12. ↑ http://investor.cempra.com/releasedetail.cfm?ReleaseID=920866. 7 July 2015 Archived 8 September 2015 at the Wayback Machine
  13. ↑ "Cempra Announces Positive Topline Phase 3 Clinical Results for Intravenous Solithromycin in the Treatment of Community-Acquired Bacterial Pneumonia (NASDAQ:CEMP)". Archived from the original on 2016-01-05. Retrieved 2016-03-03.
  14. ↑ "Cempra Announces FDA Acceptance of Solithera™ New Drug Applications in the Treatment of Community-Acquired Bacterial Pneumonia (NASDAQ:CEMP)". Archived from the original on 2016-07-09. Retrieved 2016-07-09.
  15. ↑ Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, Mankin AS (December 2010). "Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis". Antimicrobial Agents and Chemotherapy. 54 (12): 4961–4970. doi:10.1128/AAC.00860-10. PMC   2981243 . PMID   20855725.
  16. ↑ Bertrand D, Bertrand S, Neveu E, Fernandes P (December 2010). "Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors". Antimicrobial Agents and Chemotherapy. 54 (12): 5399–5402. doi:10.1128/AAC.00840-10. PMC   2981250 . PMID   20855733.
  17. ↑ Fernandes P, Martens E, Bertrand D, Pereira D (December 2016). "The solithromycin journey-It is all in the chemistry". Bioorganic & Medicinal Chemistry. 24 (24): 6420–6428. doi: 10.1016/j.bmc.2016.08.035 . PMID   27595539.
  18. ↑ Owens B (March 2017). "Solithromycin rejection chills antibiotic sector". Nature Biotechnology. 35 (3): 187–188. doi:10.1038/nbt0317-187. PMID   28267725. S2CID   3648650.
  19. ↑ "FDA Briefing Document Solithromycin Oral Capsule and Injection Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC)" (PDF). www.fda.gov. Retrieved 31 October 2017.
  20. ↑ "Cempra Annual Report". investor.cempra.com. Archived from the original on 2015-10-05. Retrieved 2017-10-30.
  21. ↑ "Cempra Receives Complete Response Letter From FDA For Solithromycin NDAs (NASDAQ:CEMP)". investor.cempra.com. Archived from the original on 2017-07-04. Retrieved 2017-10-31.
  22. ↑ "Cempra, Inc. - Annual Report". investor.cempra.com. Archived from the original on 2015-10-05. Retrieved 2017-10-30.
  23. ↑ EP 3190122,"A novel synthetic pathway towards solithromycin and purification thereof",published 2017-07-12
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