Wikipedia

Brilacidin

Brilacidin (formerly PMX-30063[2]), an investigational new drug, is a polymer-based antibiotic currently in human clinical trials, and represents a new class of antibiotics called host defense protein mimetics, or HDP-mimetics, which are non-peptide synthetic small molecules modeled after host defense peptides (HDPs).[3][4][5] HDPs, also called antimicrobial peptides, some of which are defensins, are part of the innate immune response and are common to most higher forms of life.[6][7] As brilacidin is modeled after a defensin, it is also called a defensin mimetic.[citation needed]

Brilacidin
Clinical data
Trade namesNone as of July 2012[1]
ATC code
  • none
Identifiers
  • N,N'-bis[3-{[5-(carbamimidoylamino)pentanoyl]amino}-2-[(3R)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)phenyl]pyrimidine-4,6-dicarboxamide[1]
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC40H50F6N14O6
Molar mass936.922 g·mol−1
3D model (JSmol)
  • C1CNC[C@@H]1OC2=C(C=C(C=C2NC(=O)C3=CC(=NC=N3)C(=O)NC4=CC(=CC(=C4O[C@@H]5CCNC5)NC(=O)CCCCNC(=N)N)C(F)(F)F)C(F)(F)F)NC(=O)CCCCNC(=N)N
  • InChI=1S/C40H50F6N14O6/c41-39(42,43)21-13-25(57-31(61)5-1-3-9-53-37(47)48)33(65-23-7-11-51-18-23)27(15-21)59-35(63)29-17-30(56-20-55-29)36(64)60-28-16-22(40(44,45)46)14-26(34(28)66-24-8-12-52-19-24)58-32(62)6-2-4-10-54-38(49)50/h13-17,20,23-24,51-52H,1-12,18-19H2,(H,57,61)(H,58,62)(H,59,63)(H,60,64)(H4,47,48,53)(H4,49,50,54)/t23-,24-/m1/s1
  • Key:QPDYBCZNGUJZDK-DNQXCXABSA-N

Brilacidin is an antibiotic that works by disrupting bacterial cell membranes, mimicking defensins that play a role in innate immunity.[8][9] Several mimics of antimicrobial peptides, both peptides and non-peptides, have been studied, but none have overcome difficulties to reach the market.

Structure and action

edit

Brilacidin, a non-peptide chemical mimic, is an aryl amide foldamer designed to replicate the amphiphilic properties of antimicrobial peptides while solving the problems encountered by peptide-based antimicrobials.[10] Brilacidin, a broad-spectrum antibiotic, has potent Gram positive activity and Gram negative coverage,[11] and is highly effective in treating the 'superbug' methicillin-resistant Staphylococcus aureus (MRSA). Brilacidin has low cytotoxicity against mammalian cells while selectively targeting bacteria, directly and rapidly disrupting their membranes, resulting in the bacteria's death. Due to this unique mechanism of action (mimicking the host's natural immune response, proven to be successful in fighting off infections over millions of years of evolution), bacterial antibiotic resistance is less likely to develop.[12][13][14][15]

Potential significance

edit

There has not been a new drug approval from a new class of antibiotics since 1987. While six antibiotics have been approved over the last year, they are all adaptations of existing antibiotic classes.[16] None of the recently approved novel antibiotics represent entirely new classes.[17] Novel antibiotics are crucial as antibiotic resistance poses a global health risk. The World Health Organization, warning of a "post-antibiotic era" has stated that antimicrobial resistance (AMR) is a "problem so serious that it threatens the achievements of modern medicine".[18]

History

edit

Leveraging advanced computational bioinformatics,[19][20][21] brilacidin and other defensin mimetics[22] were first developed by University of Pennsylvania-based researchers.[23][24] Their efforts were consolidated, and officially incorporated, in 2002, under the company name PolyMedix.[citation needed]

PolyMedix conducted pre-clinical and clinical research with brilacidin through a completed Phase 2a human clinical trial with positive results.[25] After discontinuing a clinical trial for an unrelated compound PolyMedix filed for Chapter 7 bankruptcy protection on 1 April 2013. Cellceutix acquired the PolyMedix assets and intellectual property, including the licenses and patents for brilacidin and the rest of the HDP-mimetic pipeline, from bankruptcy court which on 4 September 2013, approved Cellceutix's stalking horse bid.[26][27]

On 7 June 2017, Cellceutix Announced a Company Name Change to Innovation Pharmaceuticals Inc.[28] On 9 June 2017, the stock ticker name was effectively changed to "IPIX".[29]

Clinical trials

edit

Innovation Pharmaceuticals advanced brilacidin through early stage human clinical trials to a completed Phase 2a proof-of-concept clinical trial. Since acquisition, brilacidin was entered into a Phase 2b clinical trial. Brilacidin was granted the Qualified Infectious Disease Product (QIDP) designation by the FDA under the Generating Antibiotic Incentives Now Act of 2011 (GAIN Act).[30]

Phase 2a clinical trial – ABSSSI

edit

Initial Treatment for Acute Bacterial Skin Infections (ABSSSI) Caused by Staphylococcus aureus[31] Randomized, Dose Ranging, Active Controlled Efficacy and Safety Evaluation of PMX-30063 As Initial Treatment for Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Caused by Staphylococcus aureus[citation needed]

The study started in October 2010 and had a primary completion date of December 2011 for final data collection for the primary outcome measure. Overall, 215 patients were randomized into either one of the three brilacidin arms or the active comparator Daptomycin arm. There were three dosing regimens for brilacidin, a low, medium and high dose administered for three days, and one dosing regimen for Daptomycin administered for seven days.[32]

The clinical trial was successful, demonstrating safety and clinical efficacy for all evaluated doses of brilacidin, with three-day brilacidin cure rates of all dosing regimens comparable with seven days of Daptomycin. The results indicated the potential for a shorter brilacidin dosing regimen.[33] Shorter dosing regimens are important as they reduce the risks from Intravenous therapy complications, reduce costs such as reduced hospital stays and clinic visits, and can help reduce the emergence of antibiotic resistance through a combination of a quick bacterial kill, shorter duration of treatment,[34] and increased patient compliance.

Phase 2b clinical trial – ABSSSI

edit

Efficacy and Safety Study of Brilacidin to Treat Serious Skin Infections[35]

The study started February 2014 and announced completed enrollment 19 August 2014. Overall, 215 patients were randomized to one of three dosing regimens of brilacidin (single dose 0.6 mg/kg; single-dose 0.8 mg/kg; 1.2 mg/kg over 3 days) or 7 days of once daily daptomycin.[35] finding that a single dose brilacidin was comparable to 7 days of daptomycin. The primary endpoint was clinical success in the intent-to-treat population, defined as reduction of at least 20% in area of the ABSSSI lesion, relative to baseline, when observed 48–72 hours after the first dose of study drug, and no rescue antibiotics administered.[citation needed]

Phase 2 clinical trial – oral mucositis

edit

The brilacidin trial for oral mucositis (Briladidin-OM) has started in May 2015 and is expected to be completed in December 2017.[36] Brilacidin-OM is an oral rinse of brilacidin in water. Approximately 60 patients who received chemoradiation for head and neck cancer were randomized to receive either brilacidin-OM or the placebo three times daily for seven weeks. Various primary and secondary outcome measures were recorded to assess efficacy of brilacidin-OM to prevent or reduce the severity of oral mucositis in patients receiving chemo-radiation.[36]

Phase 2 clinical trial – Covid-19 / SARS-CoV-2

edit

The Brilacidin trial for the treatment of COVID-19 infection has started in February 2021 and is expected to be completed in July 2021.[37] The study is a randomized, blinded, placebo-controlled, parallel group design and will accept 120 patients. The placebo or drug will be administered via IV infusion to patients with moderate to severe COVID-19, SARS-CoV-2 infection confirmed by positive standard polymerase chain reaction test (or equivalent/ other approved diagnostic test) within 4 days prior to starting study treatment, and hospitalized with respiratory distress but not yet requiring high-level respiratory support.

The HDP-mimetic pipeline

edit

Development is ongoing for numerous brilacidin analogs, selected by laboratory testing of the various HDP mimetics and defensin-mimetic compounds in the antibiotic pipeline. Pre-clinical research has been shown select brilacidin analogs effective in killing a variety of important Gram-negative pathogens (the so-called superbugs), such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Acinetobacter baumannii as well as highly multi-drug resistant ndm-1-producing K. pneumoniae.[38] An abstract update on these efforts was presented at the European Congress of Clinical Microbiology and Infectious Disease (ECCMID) 2015 annual conference. The footnote links to the full presentation.[39] Other HDP-Mimetic analogs have proven effective in vitro against C. albicans and other Candida species.[40]

Also acquired with brilacidin and the HDP-mimetic pipeline were the rights to the related PolyCide family of compounds, polymeric formulations that function as antimicrobial agents. These compounds are similar to brilacidin in that they are also synthetic mimics of HDPs. These compounds have superior bacterial killing activity over triclosan and silver nitrate, common biocidal agents. PolyCide compounds could be used as additives to paints, plastics, textiles and other materials to create self-sterilizing products and surfaces.[41][42][43]

Notes

edit
  1. ^ a b "Statement on a nonproprietary name adopted by the USAN council" (PDF). American Medical Association. 25 July 2012. {{cite journal}}: Cite journal requires |journal= (help)
  2. ^ "Fact Sheet" (PDF). PolyMedix. Archived from the original (PDF) on 4 March 2016. Retrieved 23 April 2015.
  3. ^ Palermo EF (2011). "Antimicrobial Polymers: peptide-mimetic design and mechanism of action" (PDF). University of Michigan Library.
  4. ^ Palermo EF (2011). "The convergence of peptide and polymer science toward novel antibiotics" (PDF). University of Michigan Library. 158pages
  5. ^ Sgolastra F. "Design and synthesis of biomimetic compounds with pharmacological activity" (PDF). Universita' Politecnica Delle Marche.
  6. ^ Kuroda K, Caputo GA (2013). "Antimicrobial polymers as synthetic mimics of host-defense peptides". Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology. 5 (1): 49–66. doi:10.1002/wnan.1199. hdl:2027.42/94848. PMID 23076870.
  7. ^ "Designing mimics of membrane active proteins" (PDF). Accounts of Chemical Research
  8. ^ "brilacidin (formerly PMX-30063)". BioCentury BCIQ. BioCentury Publications. Retrieved 19 September 2013.
  9. ^ Butler MS, Cooper MA (June 2011). "Antibiotics in the clinical pipeline in 2011". The Journal of Antibiotics. 64 (6): 413–25. doi:10.1038/ja.2011.44. PMID 21587262.
  10. ^ Pucci MJ, Bush K (October 2013). "Investigational antimicrobial agents of 2013". Clinical Microbiology Reviews. 26 (4): 792–821. doi:10.1128/CMR.00033-13. PMC 3811234. PMID 24092856.
  11. ^ "ECCMID poster: brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications" (PDF). Celleutix. Archived from the original (PDF) on 4 March 2016. Retrieved 26 April 2015.
  12. ^ Steinstraesser L, Kraneburg UM, Hirsch T, Kesting M, Steinau HU, Jacobsen F, Al-Benna S (September 2009). "Host defense peptides as effector molecules of the innate immune response: a sledgehammer for drug resistance?". International Journal of Molecular Sciences. 10 (9): 3951–70. doi:10.3390/ijms10093951. PMC 2769137. PMID 19865528.
  13. ^ Nijnik A, Hancock R (24 February 2009). "Host defence peptides: antimicrobial and immunomodulatory activity and potential applications for tackling antibiotic-resistant infections". Emerging Health Threats Journal. 2: e1. doi:10.3134/ehtj.09.001 (inactive 2 November 2024). PMC 3167646. PMID 22460279.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  14. ^ Perron GG, Zasloff M, Bell G (January 2006). "Experimental evolution of resistance to an antimicrobial peptide". Proceedings. Biological Sciences. 273 (1583): 251–6. doi:10.1098/rspb.2005.3301. PMC 1560030. PMID 16555795.
  15. ^ "Key to antibiotic resistance Is to leave no enemies behind, says expert" (Press release). PolyMedix.
  16. ^ Theuretzbacher U (12 March 2015). "Recent FDA antibiotic approvals: good news and bad news". The Center for Disease Dynamics, Economics & Policy.
  17. ^ Dryden MS (April 2014). "Novel antibiotic treatment for skin and soft tissue infection". Current Opinion in Infectious Diseases. 27 (2): 116–24. doi:10.1097/QCO.0000000000000050. PMID 24504135. S2CID 205999844.
  18. ^ WHO (2014). Antimicrobial resistance: global report on surveillance 2014. World Health Organization. ISBN 978-92-4-156474-8. Archived from the original on 30 April 2014.
  19. ^ "NewWeapons for the Germ Wars". PSC.edu. Archived from the original on 6 September 2015. Retrieved 23 April 2015.
  20. ^ Lopez CF, Nielsen SO, Srinivas G, Degrado WF, Klein ML (May 2006). "Probing Membrane Insertion Activity of Antimicrobial Polymers via Coarse-grain Molecular Dynamics". Journal of Chemical Theory and Computation. 2 (3): 649–655. doi:10.1021/ct050298p. PMC 2577386. PMID 18985168.
  21. ^ "Nicholas Landekic Interview". 17 October 2003.twst.com
  22. ^ "Chemical mimetics of host defense proteins" (PDF). PolyMedix. Archived from the original (PDF) on 22 January 2015. Retrieved 23 April 2015.
  23. ^ "The Genius Chemist And His Assault On Mutant Killer Bacteria". Forbes. 28 January 2011.
  24. ^ "Man-made 'defensin' rips resistant bacteria apart". New Scientist.
  25. ^ "PolyMedix announces positive results from phase 2 clinical trial with PMX-30063 first-in-class defensin-mimetic antibiotic" (Press release). PolyMedix.
  26. ^ "Cellceutix Acquires PolyMedix Assets From Bankruptcy Court, Gains Ownership of Two Clinical Stage Drugs, Multiple Compounds, and Equipment Assets" (Press release). Cellceutix. Archived from the original on 20 February 2015. Retrieved 28 February 2015.
  27. ^ Cellceutix. "SEC Form S3 Filing: Cellceutix".
  28. ^ "Cellceutix Announces Company Name Change to Innovation Pharmaceuticals Inc". Innovation Pharmaceuticals Inc. 7 June 2017. Retrieved 10 March 2021.
  29. ^ "Innovation Pharmaceuticals Name and Ticker Change Effective, Replay of Shareholder Conference Call Available". Innovation Pharmaceuticals Inc. 9 June 2017. Retrieved 10 March 2021.
  30. ^ "Brilacidin receives QIDP designation from FDA" (Press release). Cellceutix. Archived from the original on 7 February 2015. Retrieved 28 February 2015.
  31. ^ "ClinicalTrials NCT01211470". ClinicalTrials.gov. 16 May 2012.
  32. ^ Mensa B, Howell GL, Scott R, DeGrado WF (September 2014). "Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16". Antimicrobial Agents and Chemotherapy. 58 (9): 5136–45. doi:10.1128/AAC.02955-14. PMC 4135847. PMID 24936592.
  33. ^ "PolyMedix Announces Positive Results From Phase 2 Clinical Trial With PMX-30063 First-in-Class Defensin-Mimetic Antibiotic" (Press release). Globe NewsWire.
  34. ^ Marc Bonten, MD; Eijkman-Winkler Institute for Medical Microbiology, Utrecht, the Netherland | Infectious Diseases, and Inflammation Archived 17 May 2013 at the Wayback Machine
  35. ^ a b "ClinicalTrials NCT020388". ClinicalTrials.gov. 24 September 2018.
  36. ^ a b Clinical trial number NCT02324335 for "Study of the Effects of Brilacidin Oral Rinse on Radiation-induced Oral Mucositis in Patients With Head and Neck Cancer (Brilacidin)" at ClinicalTrials.gov
  37. ^ Innovation Pharmaceuticals, Inc. (5 March 2021). "A Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-center Study to Evaluate the Efficacy and Safety of Brilacidin in Hospitalized Participants With COVID-19". {{cite journal}}: Cite journal requires |journal= (help)
  38. ^ "Synthetic novel host defense protein mimetics for the treatment of Gram-negative bacterial infections". European Society of Clinical Microbiology and Infectious Diseases: 2015.[permanent dead link]
  39. ^ "ECCMID Presentation: Synthetic Novel Host Defense Protein Mimetics for the Treatment of Gram-Negative Bacterial Infections" (PDF). European Society of Clinical Microbiology and Infectious Diseases. Archived from the original (PDF) on 4 March 2016. Retrieved 26 April 2015.
  40. ^ "In Vitro activity of novel biomimetic compounds against oral Candida strains" (PDF). New Jersey Dental School. Archived from the original (PDF) on 3 March 2016. Retrieved 2 May 2015.
  41. ^ "Synthetic polymer mimics antimicrobial properties of host-defense proteins". Qmed. Archived from the original on 18 May 2015. Retrieved 23 April 2015.
  42. ^ "Plastics Engineering". 15 February 2011. Archived from the original on 18 May 2015. Retrieved 23 April 2015.
  43. ^ "Data showing effectiveness of PolyCide antimicrobial in surgical suture coatings published in American Chemical Society Journal, Langmuir" (Press release). Globe NewsWire.

References

edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=Brilacidin&oldid=1254885228"