Brilacidin (PMX 30063)
(Synonyms: PMX 30063) 目录号 : GC32238Brilacidin (PMX 30063) (PMX 30063) 是一种抗感染抗菌剂,MIC90 为 1 和 8 μ;g/mL 用于革兰氏阳性细菌肺炎链球菌和草绿色链球菌,MIC90 为 8 和 4 μ;g/mL 用于革兰氏-阴性细菌流感嗜血杆菌和铜绿假单胞菌。
Cas No.:1224095-98-0
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | All susceptibility testing is performed by adding 90 μL of bacterial inoculum to 10 μL of 10× serial concentrations of Brilacidin into rows of a 96-well polypropylene plate. Each plate can test 8 bacterial isolates with each row containing a positive growth control and 11 serial dilutions. The diluent of Brilacidin contains 0.01% acetic acid and 0.2% bovine serum albumin. Polypropylene tubes, pipettes, and pipette tips are used to avoid binding of Brilacidin. A 1% stock of Brilacidin is diluted to 1,280 μg/mL and this is serially diluted 2-fold for 10 times to provide testing concentrations. PA and SM are tested starting at 128 μg/mL and ending at 1.25 μg/mL. All other bacteria are tested starting at 64 μg/mL and ending at 0.625 μg/mL. MICs are determined visually by locating the lowest concentration of Brilacidin that inhibits visible bacterial growth (pellet formation). The MICs are tabulated for each bacterial group and reported as MIC50, MIC90, and a range from the lowest to highest MIC[1]. |
Animal experiment: | Rabbits[1] Ocular toxicity was evaluated with 5 concentrations (1%, 0.5%, 0.25%, 0.1%, and 0.01%) of Brilacidin, formulated in Tris-buffered saline (TBS) using the Draize scoring system in the NZW rabbit ocular irritation model. The Draize Scale grades for toxicity to: cornea (opacity-degree of density, area involved), iris, and conjunctiva (redness, chemosis, and discharge). Two rabbits are tested for each Brilacidin concentration and TBS (vehicle control). Rabbits are treated in both eyes with (37 μL) topical drops every 30 min for 3 h (7 total doses). Rabbits are evaluated in a masked fashion for ocular toxicity. Ocular toxicity is evaluated using the Draize scoring system after treatment on day 0 for acute toxicity and on day 4 post treatment for any delayed toxicity. Maximum mean total scores (MMTS) are calculated and eye irritation is classified. |
References: [1]. Kowalski RP, et al. An Independent Evaluation of a Novel Peptide Mimetic, Brilacidin (PMX30063), for Ocular Anti-infective. J Ocul Pharmacol Ther. 2016 Jan-Feb;32(1):23-7. |
Brilacidin is a nonpeptidic anti-infective in a new class of defensin mimetics that is being developed for the treatment of eye infections.
Both Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) have the lowest minimum inhibitory concentrations among the bacterial groups. The MIC90s to Brilacidin for Streptococcus pneumonia (SP), Streptococcus viridians (SV), Moraxella (MS), Haemophilus influenza (HI), Pseudomonas aeruginosa (PA), and Serratia marcescens (SM) are 4, 32, 256, 32, 16, and 128-fold higher, respectively, than SA and SE. Brilacidin has Gram-positive in vitro activity; topical Brilacidin 0.5% is minimally irritating; and Brilacidin 0.5% was equally efficacious as Vancomycin (VAN) in a methicillin-resistant S. aureus (MRSA) keratitis model when the corneal epithelium is removed. Brilacidin acts primarily on the bacterial cell membrane by depolarization. Brilacidin is more potent for Gram-positive bacteria (except SV) than Gram-negative bacteria[1].
Brilacidin demonstrates dose-dependent ocular toxicity after 7 topical instillations (every 30 min for 3 h) in the NZW rabbit ocular toxicity model. Brilacidin 1% is determined to be Mildly Irritating (23.0), Brilacidin 0.5% (6.5), and Brilacidin 0.25% (4.0) are determined to be Minimally Irritating, while Brilacidin 0.1% (2.0) and TBS (1.0) are determined to be Practically Nonirritating and 0.01% Brilacidin (0.5) is determined to be Nonirritating based on their Maximum mean total scores (MMTS) values[1].
[1]. Kowalski RP, et al. An Independent Evaluation of a Novel Peptide Mimetic, Brilacidin (PMX30063), for Ocular Anti-infective. J Ocul Pharmacol Ther. 2016 Jan-Feb;32(1):23-7.
Cas No. | 1224095-98-0 | SDF | |
别名 | PMX 30063 | ||
Canonical SMILES | O=C(C1=NC=NC(C(NC2=CC(C(F)(F)F)=CC(NC(CCCCNC(N)=N)=O)=C2O[C@H]3CNCC3)=O)=C1)NC4=CC(C(F)(F)F)=CC(NC(CCCCNC(N)=N)=O)=C4O[C@H]5CNCC5 | ||
分子式 | C40H50F6N14O6 | 分子量 | 936.91 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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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 |
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Brilacidin, a Non-Peptide Defensin-Mimetic Molecule, Inhibits SARS-CoV-2 Infection by Blocking Viral Entry
EC Microbiol 2022 Apr;18(4):1-12.PMID:35695877doi
Brilacidin (PMX-30063), a non-peptide defensin-mimetic small molecule, inhibits SARS-CoV-2 viral infection but the anti-viral mechanism is not defined. Here we determined its effect on the specific step of the viral life cycle. Brilacidin blocked SARS-CoV-2 infection but had no effect after viral entry. Brilacidin inhibited pseudotyped SARS-CoV-2 viruses expressing spike proteins from the P.1 Brazil strain and the B.1.1.7 UK strain. Brilacidin affected viral attachment in hACE2-dependent and independent manners depending on the concentrations. The inhibitory effect on viral entry was not mediated through blocking the binding of either the spike receptor-binding domain or the spike S1 protein to hACE2 proteins. Taken together, Brilacidin inhibits SARS-CoV-2 infection by blocking viral entry and is active against SARS-CoV-2 variants.
Brilacidin, a COVID-19 drug candidate, demonstrates broad-spectrum antiviral activity against human coronaviruses OC43, 229E, and NL63 through targeting both the virus and the host cell
J Med Virol 2022 May;94(5):2188-2200.PMID:35080027DOI:10.1002/jmv.27616.
Brilacidin, a mimetic of host defense peptides (HDPs), is currently in Phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that Brilacidin has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inactivating the virus. In this study, we discovered an additional mechanism of action of Brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on the host cell surface. Brilacidin, but not acetyl Brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, an HSPG mimetic, abolishes the inhibitory activity of Brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that Brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that Brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on the host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that Brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of Brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.
Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture
Viruses 2021 Feb 9;13(2):271.PMID:33572467DOI:10.3390/v13020271.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than two million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin-a de novo designed synthetic small molecule that captures the biological properties of HDPs-on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is likely to be a result of the impact of Brilacidin on viral entry and its disruption of viral integrity. Brilacidin demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that Brilacidin exerts potent inhibition of SARS-CoV-2 against different strains of the virus in cell culture.
Mimics of Host Defense Proteins; Strategies for Translation to Therapeutic Applications
Curr Top Med Chem 2017;17(5):576-589.PMID:27411325DOI:10.2174/1568026616666160713130452.
New infection treatments are urgently needed to combat the rising threat of multi-drug resistant bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins (HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at multiple targets and their repertoire includes disruptive membrane and intracellular activities against numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these novel activities are associated with a low potential for emergence of resistance and little crossresistance with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candidates for new antibiotics; however, their development has been plagued by the many therapeutic limitations associated with natural peptidic agents. This review focuses on HDP mimetic approaches aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early efforts with 尾-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but demonstrated that antimicrobial activity was modulated by more, complex structural properties. Several approaches have used lipidation to increase the hydrophobicity and membrane activity. One lead compound, LTX-109, has entered clinical study as a topical agent to treat impetigo and nasal decolonization. In a more significant departure from the amino acid like peptidomimetics, considerable effort has been directed at developing amphiphilic compounds that recapitulate the structural and biological properties of HDPs on small abiotic scaffolds. The lead compound from this approach, Brilacidin, has completed two phase 2 studies as an intravenous agent for skin infections.
Comparative mechanistic studies of Brilacidin, daptomycin, and the antimicrobial peptide LL16
Antimicrob Agents Chemother 2014 Sep;58(9):5136-45.PMID:24936592DOI:10.1128/AAC.02955-14.
Brilacidin (PMX30063) has shown potent bactericidal activity against drug-resistant and -susceptible strains of multiple Gram-negative and Gram-positive pathogens. In this study, we demonstrate that Brilacidin causes membrane depolarization in the Gram-positive bacterium Staphylococcus aureus, to an extent comparable to that caused by the lipopeptidic drug daptomycin. Transcriptional profiling of Staphylococcus aureus by deep sequencing shows that the global response to Brilacidin treatment is well correlated to those of treatment with daptomycin and the cationic antimicrobial peptide LL37 and mostly indicates abrogation of cell wall and membrane functions. Furthermore, the upregulation of various chaperones and proteases by Brilacidin and daptomycin indicates that cytoplasmic protein misfolding stress may be a contributor to the mechanism of action of these drugs. These stress responses were orchestrated mainly by three two-component systems, GraSR, VraSR, and NsaSR, which have been implicated in virulence and drug resistance against other clinically available antibiotics.