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| Targets |
Brilacidin targets bacterial and viral cell membranes through a dual mechanism of action. It selectively destabilizes bacterial and viral membrane integrity, which leads to proteolysis and degradation of the pathogen. This membrane-disruptive mechanism mimics the action of defensins, which are part of the innate immune response and act as the first line of defense against foreign pathogens. Brilacidin's mechanism is rapidly bactericidal and active against stationary phase bacteria, and it requires only short treatment courses (1-3 doses). The compound's non-specific membrane-targeting mechanism makes it less susceptible to resistance development compared to conventional antibiotics that target specific proteins or enzymes.
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| ln Vitro |
Among the bacterial groupings, Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) exhibited the lowest minimum inhibitory concentrations. Brilacidin exhibits efficacious activity against Moraxella spp., Streptococcus pneumoniae (SP), and Streptococcus viridans (SV). The MIC90 values for MS, HI, PA, SM, and Haemophilus influenzae were 4, 32, 256, 32, 16, and 128 times greater than those for SE and SA, respectively. In vitro, Brilacidin demonstrates Gram-positive activity. Topical application of Brilacidin 0.5% causes minimal irritation. In a methicillin-resistant Staphylococcus aureus (MRSA) keratitis model, Brilacidin 0.5% is equally effective as vancomycin (VAN) following corneal epithelial ablation. Brilacidin mainly depolarizes bacterial cell membranes in order to effect them. Compared to Gram-negative bacteria, Brilacidin is more efficient against Gram-positive bacteria (except from SV) [2].
In vitro, brilacidin displays potent activity against a panel of drug-resistant strains. It inhibits 50% of Neisseria gonorrhoeae strains tested (MIC50) at a concentration of 4 µg/mL. Brilacidin is active against both antibiotic-sensitive and antibiotic-resistant isolates, with no significant difference in activity between them. The compound exhibits broad-spectrum antibacterial activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Brilacidin also demonstrates antiviral activity against human coronaviruses OC43, 229E, and NL63 through mechanisms targeting both the virus and the host cell. The rapid bactericidal activity of brilacidin distinguishes it from bacteriostatic antibiotics that merely inhibit bacterial growth. |
| ln Vivo |
Brilacidin showed dose-dependent ocular damage after 7 local instillations (every 30 minutes for 3 hours) in the NZW rabbit ocular toxicity paradigm. Brilacidin 1% was determined to be mildly irritating (23.0), Brilacidin 0.5% (6.5) and Brilacidin 0.25% (4.0) were considered to be mildly irritating, while Brilacidin 0.1% (2.0) and TBS (1.0) were determined to be slightly irritating. Irritating. Practically non-irritating and 0.01% Brilacidin (0.5) was determined to be non-irritating based on the Maximum Mean Total Score (MMTS) value [2].
In vivo, brilacidin has been evaluated in clinical trials for multiple indications. Phase 2 trials have been completed for treating skin infections (ABSSSI), oral mucositis, and COVID-19. In ABSSSI trials, brilacidin demonstrated efficacy comparable to standard-of-care antibiotics. For oral mucositis, brilacidin is being investigated for the supportive care of mucositis, stomatitis, and mouth diseases in patients with head and neck neoplasms. The compound's rapid bactericidal activity and short treatment duration make it particularly attractive for acute infections. Brilacidin's dual mechanism of action, targeting both bacterial membranes and host cell pathways, may contribute to its efficacy against viral infections including COVID-19. |
| Enzyme Assay |
The mechanism of brilacidin is evaluated using membrane disruption assays. Bacterial membrane integrity is assessed by measuring the release of intracellular contents (e.g., ATP, nucleic acids, proteins) following treatment with brilacidin. Fluorescent probes such as SYTOX Green or propidium iodide are used to monitor membrane permeability in real-time. Liposome leakage assays using synthetic lipid vesicles are employed to study the membrane-disrupting activity of brilacidin in a simplified system. These assays provide mechanistic insights into how brilacidin interacts with and disrupts pathogen membranes.
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| Cell Assay |
Brilacidin is tested on cultured bacterial and mammalian cells. Minimum inhibitory concentration (MIC) assays are performed using broth microdilution methods following Clinical and Laboratory Standards Institute (CLSI) guidelines. Bacterial cells are incubated with varying concentrations of brilacidin, and growth inhibition is measured by optical density or colony counting. Cytotoxicity is assessed on mammalian cell lines (e.g., human keratinocytes, fibroblasts) using MTT or LDH release assays to evaluate the therapeutic index. Time-kill assays are performed to characterize the bactericidal kinetics of brilacidin. These cell-based assays are critical for determining the potency, spectrum of activity, and safety of brilacidin.
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| Animal Protocol |
Brilacidin has been evaluated in animal models of infection and in human clinical trials. In preclinical studies, brilacidin was tested in mouse models of skin and soft tissue infection, demonstrating dose-dependent reduction in bacterial burden. Pharmacokinetic-pharmacodynamic studies were conducted to establish dosing regimens. The compound has completed Phase 2 clinical trials for ABSSSI, oral mucositis, and COVID-19. In these trials, safety, tolerability, and efficacy endpoints were evaluated. The clinical development program for brilacidin includes evaluation of intravenous and topical formulations.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of brilacidin have been conducted in both preclinical species and humans. The compound exhibits favorable pharmacokinetic properties, including good bioavailability and tissue distribution. In clinical trials, brilacidin has been administered intravenously, with pharmacokinetic parameters characterized including half-life, volume of distribution, and clearance. The compound achieves therapeutic concentrations at sites of infection. The pharmacokinetic profile of brilacidin supports short-course dosing regimens (1-3 doses). Food effects and drug-drug interaction potential have been evaluated as part of the clinical development program.
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| Toxicity/Toxicokinetics |
In clinical trials, brilacidin has been shown to be generally well-tolerated. The safety profile is consistent with its mechanism of action as a membrane-active agent. Common adverse effects observed in clinical trials include mild-to-moderate infusion site reactions and gastrointestinal disturbances. Serious adverse events are uncommon. The compound's selectivity for bacterial membranes over mammalian cell membranes contributes to its favorable safety profile. Long-term safety data is being collected as part of ongoing clinical development.
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| References |
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| Additional Infomation |
Brilacidin is being investigated for use as adjunctive therapy for mucositis, stomatitis, oral diseases, and head and neck tumors. Brilacidin is a synthetic, non-peptide small molecule that mimics defensins (host defense proteins/peptides (HDPs) or antimicrobial peptides (AMPs)) and possesses potential antibacterial and antiviral activity. Upon administration, brilacidin selectively disrupts the cell membrane integrity of bacteria and viruses, leading to their proteolysis and degradation. HDPs are part of the innate immune response and form the first line of defense against foreign pathogens. Studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inhibits defensin production.
Brilacidin is a host defense protein mimetic (HDP-mimetic) antibiotic that has completed Phase 2 clinical trials. It has been investigated for ABSSSI caused by S. aureus, oral mucositis, and COVID-19. Brilacidin's dual mechanism of action—disrupting pathogen membranes and modulating host immune responses—represents a novel approach to anti-infective therapy. The compound's rapid bactericidal activity, broad-spectrum activity, and low propensity for resistance make it a promising candidate for treating multidrug-resistant infections. Brilacidin is also being explored for its antiviral activity, with evidence of activity against human coronaviruses. Ongoing research continues to evaluate the full therapeutic potential of brilacidin across multiple indications. |
| Molecular Formula |
C40H50F6N14O6
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|---|---|
| Molecular Weight |
936.91
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| Exact Mass |
936.394
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| CAS # |
1224095-98-0
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| Related CAS # |
Brilacidin tetrahydrochloride;1224095-99-1
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| PubChem CID |
25023695
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
8.479
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| Hydrogen Bond Donor Count |
10
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| Hydrogen Bond Acceptor Count |
18
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
66
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| Complexity |
1560
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| Defined Atom Stereocenter Count |
2
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| SMILES |
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)CCCCN=C(N)N)C(F)(F)F)C(F)(F)F)NC(=O)CCCCN=C(N)N
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| InChi Key |
QPDYBCZNGUJZDK-DNQXCXABSA-N
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| InChi Code |
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
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| Chemical Name |
4-N,6-N-bis[3-[5-(diaminomethylideneamino)pentanoylamino]-2-[(3R)-pyrrolidin-3-yl]oxy-5-(trifluoromethyl)phenyl]pyrimidine-4,6-dicarboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0673 mL | 5.3367 mL | 10.6734 mL | |
| 5 mM | 0.2135 mL | 1.0673 mL | 2.1347 mL | |
| 10 mM | 0.1067 mL | 0.5337 mL | 1.0673 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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