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Trade names | None as of July 2012 [1] |
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Formula | C40H50F6N14O6 |
Molar mass | 936.922 g·mol−1 |
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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 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.
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]
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]
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]
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]
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.
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 ]
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]
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.
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]
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(help)An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the ones which cause the common cold or influenza; drugs which inhibit growth of viruses are termed antiviral drugs or antivirals rather than antibiotics. They are also not effective against fungi; drugs which inhibit growth of fungi are called antifungal drugs.
Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally as a treatment for severe Clostridium difficile colitis. When taken orally it is poorly absorbed.
Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.
Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively replaced by the use of antibiotics in most parts of the world after the Second World War. Bacteriophages, known as phages, are a form of virus that attach to bacterial cells and inject their genome into the cell. The bacteria's production of the viral genome interferes with its ability to function, halting the bacterial infection. The bacterial cell causing the infection is unable to reproduce and instead produces additional phages. Phages are very selective in the strains of bacteria they are effective against.
Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.
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.
Fusidic acid, sold under the brand names Fucidin among others, is an steroid 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.
Daptomycin, sold under the brand name Cubicin among others, is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms.
Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct antimicrobial activity, immune signaling activities, or both. They are variously active against bacteria, fungi and many enveloped and nonenveloped viruses. They are typically 18-45 amino acids in length, with three or four highly conserved disulphide bonds.
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antimicrobials which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.
In microbiology, the minimum inhibitory concentration (MIC) is the lowest concentration of a chemical, usually a drug, which prevents visible in vitro growth of bacteria or fungi. MIC testing is performed in both diagnostic and drug discovery laboratories.
Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).
Polypeptide antibiotics are a chemically diverse class of anti-infective and antitumor antibiotics containing non-protein polypeptide chains. Examples of this class include actinomycin, bacitracin, colistin, and polymyxin B. Actinomycin-D has found use in cancer chemotherapy. Most other polypeptide antibiotics are too toxic for systemic administration, but can safely be administered topically to the skin as an antiseptic for shallow cuts and abrasions.
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.
Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses. The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues. Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues. Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.
Solithromycin is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia and other infections.
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.
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.
Murepavadin also known as POL7080 is a Pseudomonas specific peptidomimetic antibiotic. It is a synthetic cyclic beta hairpin peptidomimetic based on the cationic antimicrobial peptide protegrin I (PG-1) and the first example of an outer membrane protein-targeting antibiotic class with a novel, nonlytic mechanism of action, highly active and selective against the protein transporter LptD of Pseudomonas aeruginosa. In preclinical studies the compound was highly active on a broad panel of clinical isolates including multi-drug resistant Pseudomonas bacteria with outstanding in vivo efficacy in sepsis, lung, and thigh infection models. Intravenous murepavadin is in development for the treatment of bacterial hospital-acquired pneumonia and bacterial ventilator-associated pneumonia due to Pseudomonas aeruginosa.
Kerry L. LaPlante is an American pharmacist, academic and researcher. She is the Dean at the University of Rhode Island College of Pharmacy. She is a Professor of Pharmacy and former department Chair of the Department of Pharmacy Practice at the University of Rhode Island, an Adjunct Professor of Medicine at Brown University, an Infectious Diseases Pharmacotherapy Specialist, and the Director of the Rhode Island Infectious Diseases Fellowship and Research Programs at the Veterans Affairs Medical Center in Providence, Rhode Island.