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ABSTRACT 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.

12 Sep 2013·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Expedient Synthesis of SMAMPs via Click Chemistry

Q3 · MEDICINE

Article

Author: Fu, Tsung-hao ; Thaker, Hitesh D. ; Li, Yan ; Tew, Gregory N. ; Scott, Richard W.

A novel series of synthetic mimics of antimicrobial peptides (SMAMPs) containing triazole linkers were assembled using click chemistry. While only moderately active in buffer alone, an increase in antimicrobial activity against Staphylococcus aureus and Escherichia coli was observed when these SMAMPs were administered in the presence of mouse serum. One compound had minimum inhibitory concentrations (MICs) of 0.39 μg/mL and 6.25 μg/mL, respectively, and an HC50 of 693 μg/mL. These values compared favorably to peptide-based antimicrobials. A correlation between the net positive charge and SMAMP antimicrobial activity was observed. The triazole linker, an amide surrogate, was found to provide better antimicrobial activity against both S. aureus and E. coli when compared to other analogues.

20 May 2012·Journal of Clinical Oncology

Evaluation of a non-peptidic mimic of host defense proteins, PMX30063, in an animal model of oral mucositis.

Author: Korczak, Bozena ; Sonis, Stephen T. ; Scott, Richard W ; Watkins, Brynmor A

9119 Background: Oral ulcerative mucositis (OM) is a common, painful, dose-limiting toxicity of cancer therapy. The care for OM is largely palliative and there is an urgent need for new and effective therapies. Host defense proteins (HDPs) are amphiphilic components of the innate immune system that serve as a primary response to infection. Exclusive of their direct antimicrobial activity, HDPs have been shown to possess immune modulatory and anti-inflammatory activities. We are developing non-peptidic mimics of HDPs, capturing the structural and biological properties of HDPs within a framework of smaller fully synthetic oligomers. The lead compound, PMX30063, is in Phase 2 clinical trials for iv treatment of systemic staphylococcal infections. Recently, we observed that HDP mimics attenuate anti-inflammatory pathways and reasoned that these activities could be leveraged into a mucositis intervention. Methods: In an acute radiation hamster model, PMX30063 was applied as a topical rinse, 3 times daily at 1, 3 or 10 mg/ml over a 28 day treatment regimen ( n = 10), following a single radiation dose to the buccal cheek pouch (40 Gy). In a fractionated radiation model, radiation (7.5 Gy/dose) was administered on days 0, 1, 2, 3, 6, 7, 8 and 9, targeting the left buccal pouch mucosa. PMX30063 was given topically 3 times daily at 3 mg/ml over a 35 day regimen beginning on day 0 (n = 10). OM was scored using an established blinded method. Results: In the acute model, PMX30063 reduced the number of animal days with ulceration from 43% in vehicle-treated hamsters to < 5% in all 3 PMX30063 dose groups (χ2 test; p<0.001). In the fractionated model, PMX30063 significantly reduced the daily mucositis scores prior to peak mucositis and throughout the remaining course of treatment (Mann-Whitney Rank-sum analysis; p<0.001). PMX30063 reduced the number of animal days with ulceration from 55% in vehicle-treated hamsters to 3.3% (χ2 test; p<0.001). The time courses of efficacy argue that direct antimicrobial action is not the primary driver of efficacy. Conclusions: The safe and highly efficacious activity of PMX30063 in animals supports its further development as a topical therapeutic to prevent OM in cancer patients.

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100 Translational Medicine associated with PolyMedix, Inc.

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Pipeline

Pipeline Snapshot as of 24 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

PMX-07	Stomatitis More	Discontinued
Delparantag ( Heparin )	Coronary Artery Disease More	Discontinued
PMX-741	Bacterial Infections More	Discontinued
Brilacidin ( SARS-CoV-2 antigen )	Skin and skin structure infections More	Pending
Angiogenesis Inhibitors (Innovation Pharmaceuticals)	Neoplasms More	Pending