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What happened to your Feb 6th proclamation...
of "a significant positive press release in 6-8 weeks that will move the share price big-time whereby investors on the sideline would be scrambling to buy IPIX"?
Or was this just another fail in a long list of failed prognostications? As many times as you've faceplanted you must look like a pug.
Questions that are never answered. He/she sounds a lot like early years Leo before he vanished...big on hype/hope with little to no delivery.
Why don't you tell us what is positive about a .000 to .00 stock? This mess has been completely decimated and what is left is a one-person company, with only one board member who is also the only person in the company, where the shares cannot even be traded on the lowly pink sheets but are on some "expert" wasteland, where, consequently, there is little no volume and where most accounts will not allow you to buy the shares, where the "company" was hit with a major judgement that put it in the red and which came about because the CEO was asleep-at-the-wheel, where there is no longer any communication from the CEO to shareholders or any avenue for communication, where the one-man company maintains a website filled with stale information that has become misinformation, where there are no longer any filings and no transparency, where efforts to license or sell or achieve any degree of profitability from its one remaining drug have all failed (Locust Walk, Alfasigma, etc.), and where the CEO spent $4 million from his cash strapped mess to buy into some laser company where transparency is lacking and there is virtually no information about the financial status of that company (costs v anticipated sales, anticipated income, profitability projections, etc.). A dirty shell is all that is left.
Anything positive about IPIX is a figment of your imagination.
Anything positive about IPIX must be killed. Remember, the company is "dead."
Interesting when Frenchy posts, there is a direct attack on him all the time.....why is that????
"Thank you for this Schwab information. If it is true and I can buy I will make a new account."
Did you find it to be true? (I don't care if you made a new account.)
And what happened to this?
Have you managed to scoop up those 3 million shares yet?
And where are those promising press releases you were boasting about in June of last year? You can't even find the vanished CEO let alone any positive press releases. Doesn't look like there is much of anything left now.
If it so promising, why has no interest materialized? Do you really think an idiot like Erhlich can get anything promising accomplished? Look at the mess he has left this company in.
News flash - there’s no market for IPIX or B. Dead.
I'm guess I'm not so concerned with IPIX license agreement with having William Degrado still on board. I figure if UP wanted B back they could have rescued it out of Polymedix bankruptcy. It was good to see the latest peer review stating William DeGrado's contributions to B's anti-fungal studies. We have anti-fungal testing here and in Brazil. Hopefully something positive comes out of this for those holding shares.
I agree that there's a lot of interest in anti-fungal drugs particularly if continued climate change will increase and possibly compound the issue.
While I believe that B showing promise is the legitimate driver I'm wondering if applying for a patent is regarded simply as a way of placing a marker on what could be a promising drug. Also, there has to be an awareness of B nearing the end of license and does that have anything to do with the surge in patents?
I would hate for B to be swooped up by someone after IPIX investors have spent so much time and money pushing it to the 49 yard line. It would suck to have to watch some pharma with money, resources, and FDA influence spike 'our' B in the end zone.
Leo did not demonstrate well in his management of the office lease. Over the past few years I do not feel Leo has been putting forth the effort to advance B as his compensation should warrant. I guess we wait and see if Leo has the capability and the motivation to pursue bringing B to some degree of fruition.
I would think an effective new anti-fungal combination of Bril + Caspofungin would be of great interest to BP
Come on Leo, sell it all for .50!
Looks to be a new patent app combining/using Bril + Caspofungin?
Does anyone know what the fee is for filing a patent application such as the one PJ007 posted? A cursory look indicated that a "non-electronic" application is $200-$400 and getting a patent approved spins up numbers between $8 - $15k all the way to pharmaceutical patents costing over $2M.
What I'm trying to determine is a degree of seriousness behind these patent applications. If it's just a few dollars for an online application it could be somewhat frivolous, a low budget attempt to cover all bases, or a desire to muddy the waters. If it's the University of Sao Paulo I imagine there would be some justification required before spending even a few hundred dollars. Universities tend to be frugal with research expenditures.
I understand that there are obstacles beyond the patent office and would appreciate if responses centered on what the application stage costs.
I don't know but I sure would love to know.....
Good catch, why do you think another patent has been secured? Preparing for a sale?
Well I want to know where the frick Leo is? Pathetic he has just disappeared
wow, another patent published today on Brilacidin
https://ppubs.uspto.gov/dirsearch-public/print/downloadPdf/20240139188
What is going on ???
I tried to call BM via what’s app and could not get through..
He has been mostly missing from access to stock holders for quite a while. But the real disgrace, imo. is not that, it is the million plus he and a friend have been extracting annually, these last few years. Lots of money for a company with no office, no lab, no post docs, no news letter, etc. He has tried to enhance value a few times, and that is to his credit; but the fact that we here have subsidized his stock play with nothing to show for it but losses, is the problem, not denying his general absence remains a disgrace, to use your words.
Waldo Ehrlich has completely vanished. What a disgrace.
I don't have either notation but they look like footnotes. Are 3 and 4 described further down the page?
That does make sense… but why 3 and 4
Interesting, phone has a 3 and PC has a 4 that’s the only position in all my investments that has those numbers
What page are you looking at? My Schwab account doesn't have that notation on the Position page....phone or computer.
Perhaps it’s referring to decimal position?
Might mean 4 days left until a total loss. See if the number changes to (3) tomorrow and report back.
Question: what does the little 4 mean on my Charles Schwab $0.0015(4)
ABSSSI - In February 2016, the Company submitted a Special Protocol Assessment (SPA) request, along with a final protocol, to the FDA, for a Phase 3 clinical trial of Brilacidin for the treatment of Acute Bacterial Skin and Skin Structure Infection (ABSSSI) caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). We received from the FDA comments and considerations for incorporation into our study design. Management decided to delay its response to the FDA due to the low price per share of our common stock and the many multiple million dollar costs associated with a Phase 3 program. Our strategy, for now, is to achieve success with other trials and attract partnering opportunities that may provide significant upfront payments and milestone payments, which can then be used to fund the ABSSSI program. We see ABSSSI as the appropriate gateway indication in infectious diseases, enabling potential further studies of Brilacidin’s use for implant coating and biofilm infections.
https://www.sec.gov/ix?doc=/Archives/edgar/data/1355250/000147793223007158/ipix_10k.htm (2023 10-K)
Warning! This security is traded on the Expert Market
The Expert Market® serves broker-dealer pricing and investor best execution needs. Quotations in Expert Market securities are restricted from public viewing. OTC Markets Group may designate securities for quoting on the Expert Market when it is not able to confirm that the company is making current information publicly available under SEC Rule 15c2-11, or when the security is otherwise restricted from public quoting.
https://www.otcmarkets.com/stock/IPIX/overview (today)
Don't' know.
Is today's (and yesterday and the day before and the day before) posting action the paid basher model?
If this mess must still trade, it's the perfect spot for this clown company and Ehrlich, the Ringmaster of Disaster.
Fools doing this so-called tradng nowadays???? Today's trade was for a tenth of a cent. LMAO.
If they had any sense, they would let the volume be zero for months on end. This joke of a trade shows it is just a clown show.
Is today's volume/price action the R**N model?
Go to the original article.
There are two tables labeled Table 1 Brilacidin activity against problem pathogens and Table 2 Initial screen of Brilacidin activity against other problem pathogens. All you need to see them is click on the boxes with the arrows.
I haven't studied them too closely but those SEEM to be the only things that you missed. They make themselves apparent when you click the download button, as suggested.
Tell you what, why don't you press the download and post. I pulled what I could
and can pull no more with my computer.
Here it is again.
Re: SitTight post# 402646
Sunday, April 28, 2024 11:02:39
Antifungal Activity of Brilacidin, a Nonpeptide Host Defense Molecule
by David J. Larwood 1,2,3ORCID andDavid A. Stevens 2,4,*ORCID
1
Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA
2
California Institute for Medical Research, San Jose, CA 95128, USA
3
Valley Fever Solutions, Tucson, AZ 85719, USA
4
Division of Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, CA 94305, USA
*
Author to whom correspondence should be addressed.
Antibiotics 2024, 13(5), 405; https://doi.org/10.3390/antibiotics13050405 (registering DOI)
Submission received: 8 February 2024 / Revised: 16 April 2024 / Accepted: 17 April 2024 / Published: 28 April 2024
Down load key board_arrow_down Versions Notes
Abstract
Natural host defensins, also sometimes termed antimicrobial peptides, are evolutionarily conserved. They have been studied as antimicrobials, but some pharmaceutical properties, undesirable for clinical use, have led to the development of synthetic molecules with constructed peptide arrangements and/or peptides not found in nature. The leading development currently is synthetic small-molecule nonpeptide mimetics, whose physical properties capture the characteristics of the natural molecules and share their biological attributes. We studied brilacidin, an arylamide of this type, for its activity in vitro against fungi (40 clinical isolates, 20 species) that the World Health Organization has highlighted as problem human pathogens. We found antifungal activity at low concentrations for many pathogens, which indicates that further screening for activity, particularly in vivo, is justified to evaluate this compound, and other mimetics, as attractive leads for the development of effective antifungal agents.
Keywords: brilacidin; synthetic nonpeptide mimetics; antifungal activity; defensins; antimicrobial peptides; AMP
1. Introduction
Peptide antibiotics (e.g., vancomycin, daptomycin, polymyxin, echinocandins) have shown their value in clinical medicine. There are >2000 discovered natural “antimicrobial peptides” (AMPs) which are highly evolutionarily conserved and present in microbes, plants, and all vertebrates [1,2]; >100 are known to be produced by humans [3,4]. A broad antimicrobial spectrum is a group characteristic, most are amphiphilic and cationic [3]. These peptides are better termed “host defense peptides” or defensins, because they are part of the host’s innate immune response and are the first line of defense [5,6]. Many of these appear to have broad biological functions, as will be further discussed.
There has been longstanding interest in exploiting such molecules, and their analogues, as clinical anti-infectives, with stimulation to expand our armamentarium owing to the development of resistance to current chemically synthesized molecules and other natural products. Natural AMPs may be undesirable for clinical therapeutics because of instability, degradation by host proteases, low solubility, reduced activity in the presence of salts or DNA, short half-lives in vivo, difficult and expensive manufacturing issues, and the possibility of the development of antibodies in heterologous hosts [6,7,8,9,10,11]. This led to the development of synthetic AMPs, using amino acid sequences and/or amino acids not found in nature, which ameliorated some of these problems [12,13]. It was then discovered that the physicochemical properties of the synthetic molecules were more important than the sequence of the amino acids [10,11,14], and, with attention to the secondary structure, charge, and folding, that totally synthetic non-peptide molecules could recapitulate the structural properties of AMPs and mimic their activities [10,11]. A lead candidate from this line of research is brilacidin, a cationic water-soluble amphiphilic helical arylamide with discrete nonpolar hydrophobic and polar hydrophilic regions and a polymer backbone [10]. The present study is an initial exploration of the antifungal spectrum of brilacidin, with particular attention to pathogens for which there is a huge present clinical burden (e.g., cryptococcosis in Africa in the wake of the AIDS epidemic) and those pathogens for which present clinically available antifungals provide insufficient efficacy.
2. Results
The screening of the selected fungal pathogens of great interest is displayed in Table 1. The low MIC values (largely < 4 µg/mL) of all in this group, except A. fumigatus, suggests that brilacidin is worthy of study in animal models to ascertain whether this level of potency in vitro will translate into efficacy in vivo and thus have potential clinical utility. These MIC values in µg/mL are favorable compared to those of conventional antifungals.
Table 1. Brilacidin activity against problem pathogens.
There is a disparity between this 50% inhibition and the elevated 100% inhibition MICs for Coccidioides, Mucorales, Sporothrix, and Fusarium, suggesting that for those pathogens, brilacidin’s antimicrobial activity is unlike that of polyenes. Polyenes, such as amphotericin B, typically have similar concentrations for 50% and 100% inhibition and even for cidal activity [15]. However, the clinical utility of azoles and echinocandins, which also do not produce even 100% fungal inhibition in vitro, suggests that conclusions about the efficacy of brilacidin in vivo need to be deferred until animal models are explored. The most striking, consistent results are those against C. neoformans, where brilacidin appears to have unique antifungal activity among these pathogens assayed.
The studies displayed in Table 2 represent an initial screening effort to examine whether other groups of pathogens may be worthy of the broader screening displayed in Table 1. Several of these pathogens are in the favorable range discussed for pathogens studied as per Table 1 and should be more extensively screened in the future; the initial results with Nakaseomyces glabratus and Candida auris do not as yet, unfortunately, give such indication.
Table 2. Initial screen of Brilacidin activity against other problem pathogens.
3. Materials and Methods
3.1. Drugs
Brilacidin (N4, N6-bis(3-(5-gaunidinopentanamido)-2-(R)-pyrrolidin-3-yl)oxy)-5-(trifluoromethyl)phenyl)pyrimidine-4,6-dicarboxamide tetrahydrochloride) (C40H50F6N14O6.4HCl), MW 1082.7, sterile and >98% pure, was supplied by Innovation Pharmaceuticals, Wakefield, MA, USA. It was supplied as a solid and was readily soluble in water and liquid media, such as RPMI-1640. To convert µg/mL, as expressed in this paper, to millimolar, multiply µg/mL by 0.924.
In prior studies for some isolates, as mentioned, azoles were supplied by Pfizer Inc., Groton, CT, USA; echinocandins by Merck, Inc., Rahway, NJ, USA; and amphotericin B by the Bristol-Myers Squibb Company, Princeton, NJ, USA.
3.2. Isolates
The World Health Organization has recently identified particular fungal pathogens as needing attention because of epidemiological reasons and/or resistance to many available drugs [16]. It was this document that guided our selection of isolates, constrained by the availability of isolates in our collections. The isolates were all recent clinical isolates, sent to our laboratories for clinical testing, with three exceptions (CN9759, Silv., 10AF), which were originally clinical isolates but were maintained in the laboratory because they have desirable characteristics for animal model studies, which may be indicated in the future. All were tested using their CIMR accession numbers, without any patient identification.
3.3. Testing
Testing was performed by standard broth dilution methods detailed elsewhere [17,18,19]. The RPMI-1640 medium is desirable because it is fully defined and it also allows microbial susceptibility testing in the presence of mammalian cells in the future. Testing of Coccidioides was performed under BSL3 conditions. A stock solution was made of 640 µg/mL. The range of concentrations tested, in 2-fold dilutions, was 0.5–64 µg/mL. For the testing of a new drug, it is not clear whether a 50% inhibition endpoint for yeasts (equivalent to a Minimum Effective Concentration, that concentration producing a morphological change in filamentous fungi), as is used clinically for azoles and flucytosine, or a 100% inhibition endpoint (i.e., a tube as clear as the starting inoculum), as is used clinically for polyenes, is most relevant, so both endpoints were determined for brilacidin. In isolated instances where relevant (mentioned in the tables) azole resistance was defined as 50% inhibition at ≥64 µg/mL, echinocandin resistance as 50% inhibition at ≥3.1 µg/mL, and amphotericin intermediate as 100% inhibition at ≥2 µg/mL. Testing was repeated in approximately 20% of the assays and was always reproducible. Every assay included a positive concurrent control, embodying a pan-susceptible Candida kefyr, and fluconazole (MIC < 0.5 µg/mL).
4. Discussion
The activities of AMPs have been described against bacteria, protozoa, and viruses [2,20,21,22]. Several theoretical models exist to explain their interactions with cells [2,22,23]. The antifungal activity of other AMPs and their analogues has previously been demonstrated [3,4,12,13,24,25,26,27,28], including, in our prior study, against pathogens resistant to specific antifungals [13] and with cidal activity sometimes demonstrated [13,27]. A topically applied AMP has already shown antifungal efficacy in patients [23]. In the present study, conidia or yeasts were used as the inoculum. The conidia develop during the assay to hyphae; thus, in the case of filamentous organisms, antifungal activity against conidia themselves, during transformation to hyphae or on hyphal development, could produce positive test results. Prior studies have indicated AMP activity against all these phases [4,29]. Our results, with our testing methods, are consistent with the observed rapid antifungal action of AMPs [13,24]. The present study shows brilacidin activity in vitro against several problem fungal pathogens. For possible clinical interest, these studies must be expanded to further study brilacidin’s pharmacology, tissue penetration, and toxicology. What is not yet understood is why there are the species differences in susceptibility that we have demonstrated, and this may relate to differences in susceptibility to the mechanism(s) of drug action. More studies, with other fungal species, are required. Although brilacidin has been shown to depolarize the A. fumigatus cell membrane and to disrupt the cell wall [30], our results (minimal activity against this genus) present a difference from the inhibitory activity against A. fumigatus demonstrated for some AMPs [4]. A caution regarding this subject is that some AMPs have also been shown to increase A. fumigatus growth in vitro [4,27].
Prior studies have indicated the synergy in vitro of AMPs and their analogues with conventional antimicrobials and antifungals [7,8,26,28,30], even with host AMPs [8], which is an avenue for further exploration. One possible mechanism for any such synergy is that AMP increases the permeability of, and depolarization of, the pathogen membrane, allowing greater penetration of the conventional drug [6,31,32]. Brilacidin synergy with an antifungal in vivo has been shown [30].
It is unclear what in vitro test characteristics, aside from whether to use 50% or 100% endpoints, will be most useful to predict activity in vivo. Which medium is the best needs determination, as well as the conditions of pH, ionic concentration, oxygenation, and buffer [29]. It may be most relevant to study these agents in the presence of host cells, and, depending on the target in vivo, to test in a milieu that reflects the tissue situation, such as artificial sputum medium, as we have done [33]. Testing against fungal biofilms may be more relevant than against planktonic growth for many clinical situations [34], and AMPs have been demonstrated to inhibit biofilms [1,8,13,26,35].
Mechanisms of action for AMPs and their analogues include: insertion into pathogen (and host) membranes (with creation of pores) or other phospholipids and/or into ribosomal subunits, stress on protein folding, stress of cell membranes, increase of reactive oxygen species; affecting intracellular calcium concentrations, affecting the proteome, inactivation of cellular proteins; affecting cell signaling, the regulation of cell death, binding the anionic nucleic acids and/or affecting their synthesis, preventing biofilm formation, regulating iron metabolism, the inhibition of cellular enzymes, the activation of cell wall lytic enzymes, binding of glucan and/or chitin, the modulation of the cell wall to expose beta glucan, and the degradation of cell walls [1,2,3,4,6,7,8,12,23,25,27,28,36,37].
Given AMP’s effects on the regulation of many genes in their targets [6] and all these possible mechanisms of action, many effects on host function have also been described for them, including affecting host cell differentiation, immunomodulation, the regulation of cytokines, opsonization, the regulation of inflammation, the increase of phagocytosis, the stimulation of chemotaxis (for neutrophils, monocytes, and lymphocytes), the activation of eosinophils and angiogenesis, and the activation of epithelial cells [1,2,3,7,27,38]. It is likely that these possible host effects would come into play if brilacidin were to be used as an antifungal in vivo, and this may make MIC’s absolute values, or differences, in vitro less important for the effect on the outcome.
The development of resistance to AMPs has been shown generally difficult for microbes to achieve [6], and that has been corroborated for peptide AMPs [4], synthetic peptides [13], and brilacidin [10]. AMP action on several different microbial processes, as detailed above, may explain AMP’s breadth of microbial spectrum [3], as shown in our results here with various species, and AMP’s defense against resistance development [1]. Previous observations of the development of resistance to AMPs have included the development of microbial efflux pumps, which may be lessened for the nonpeptide mimetics [8]. The cationic nature of brilacidin and its water solubility may relate to its ability to target charged fungal membranes [2,11]. Brilacidin depolarization of microbial membranes and its induction of membrane and cell wall stress have been demonstrated [10].
The structure of the nonpeptide mimetics preserves the AMP theme of such biologically active molecules having both a charged face and a hydrophobic face [6,39]. The activity of these mimetics is more closely linked to their physicochemical properties than the details of the structures [40]. This nature of this class of molecules allows for studies of molecular modifications that could improve efficacy and decrease undesirable effects [12]. Its manipulation of charge, amphiphilicity, hydrophobic–hydrophilic balance, and folding properties create possibilities for the future. Presently, brilacidin is being studied in human clinical trials for other indications and is not yet focused on fungal infections.
Author Contributions
D.J.L. contributed substantially to all aspects of this project including conception, funding, execution, draft writing, and review. D.A.S. contributed substantially to all aspects of this project including conception, funding, execution, draft writing, and review. All authors have read and agreed to the published version of the manuscript.
Funding
This study was supported by funds from the University of California, San Francisco, Valley Fever Solutions, the Valley Fever Americas Foundation, the Foundation for Research in Infectious Diseases, the California Institute for Medical Research, the David and Mary Larwood Family Charitable Fund, and Innovation Pharmaceuticals.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Tables of the original raw data are available from the corresponding author.
Acknowledgments
We thank William F. DeGrado, University of California, San Francisco, for his contributions to the development of the field of nonpeptide defensin mimetics, his interest in the initiation of these studies, and his critique of the manuscript.
Conflicts of Interest
David J. Larwood is employed by Valley Fever Solutions and is a PhD candidate at the University of California, San Francisco. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
References
Mookerjee, M.; Anderson, M.A.; Haagsman, H.P.; Davidson, D.J. Antimicrobial host defense peptides: Function and clinical potential. Nat. Rev. Drug Discov. 2020, 19, 311–332. [Google Scholar] [CrossRef]
Lewies, A.; Wentzel, J.F.; Jacobs, G.; Du Plessis, L.H. The potential use of natural and structural analogues of antimicrobial peptides in the fight against neglected tropical diseases. Molecules 2015, 20, 15392–15433. [Google Scholar] [CrossRef]
Baxter, A.A.; Poon, I.K.H.; Hulett, M.D. The lure of the lipids: How defensins exploit membrane phospholipids to induce cytolysis in target cells. Cell Death Dis. 2017, 8, e2712. [Google Scholar] [CrossRef]
Ballard, E.; Yucel, R.; Melchers, W.J.G.; Brown, A.J.P.; Verweij, P.E.; Warris, A. Antifungal activity of antimicrobial peptides and proteins against Aspergillus fumigatus. J. Fungi 2020, 6, 65. [Google Scholar] [CrossRef]
de la Fuentes-Nunez, C.; Silva, O.N.; Lu, T.K.; Franco, O.L. Antimicrobial peptides: Role in human disease and potential as immunotherapies. Pharmacol. Ther. 2017, 178, 132–140. [Google Scholar] [CrossRef]
Mensa, B.; Howell, G.L.; Scott, R.; DeGrado, W.F. Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16. Antimicrob. Agents Chemother. 2014, 58, 5136–5145. [Google Scholar] [CrossRef]
Lima, P.G.; Oliveira, J.T.A.; Amaral, J.L.; Freitas, C.D.T.; Souza, P.F.N. Synthetic antimicrobial peptides: Characteristics, design, and potential as alternative molecules to overcome microbial resistance. Life Sci. 2021, 78, 119647. [Google Scholar] [CrossRef]
Li, J.; Fernandez-Millan, P.; Boix, E. Synergism between host defense peptides and antibiotics against bacterial infections. Curr. Top. Med. Chem. 2020, 20, 1238–1263. [Google Scholar] [CrossRef]
Payne, J.E.; Dubois, A.V.; Ingram, R.J.; Weldon, S.; Taggart, C.C.; Elborn, J.S.; Tunney, M.M. Activity of innate antimicrobial peptides and ivacaftor against clinical cystic fibrosis respiratory pathogens. Internat. J. Antimicrob. Agents 2017, 50, 417–435. [Google Scholar] [CrossRef]
Scott, R.W.; Tew, G.N. Mimics of host defense proteins; strategies for translation to therapeutic applications. Curr. Top. Med. Chem. 2017, 17, 576–589. [Google Scholar] [CrossRef]
Tew, G.N.; Scott, R.W.; Klein, M.L.; DeGrado, W.F. De novo design of antimicrobial polymers, foldamers and small molecules: From discovery to practical applications. Acc. Chem. Res. 2010, 43, 30–39. [Google Scholar] [CrossRef]
Lyu, Y.; Yang, Y.; Lyu, X.; Dong, N.; Shan, A. Antimicrobial activity, improved cell selectivity and mode of action of short PMAP-36-derived peptides against bacteria and Candida. Sci. Rep. 2016, 6, 27258. [Google Scholar] [CrossRef]
Woodburn, K.W.; Clemens, L.E.; Jaynes, J.; Joubert, L.-M.; Botha, A.; Nazik, H.; Stevens, D.A. Designed antimicrobial peptides for recurrent vulvovaginal candidiasis treatment. Antimicrob. Agents Chemother. 2019, 63, e02690-18. [Google Scholar] [CrossRef]
Scott, R.W.; DeGrado, W.F.; Tew, G.N. De novo designed synthetic mimics of antimicrobial peptides. Curr. Opin. Biotechnol. 2008, 19, 620–627. [Google Scholar] [CrossRef]
Stevens, D.A.; Hope, W. Polyene antifungals. In Principles and Practice of Infectious Disease, 10th ed.; Blaser, M.J., Cohen, J.I., Holland, S.M., Eds.; Elsevier: Philadelphia, PA, USA, in press.
World Health Organization. WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action; World Health Organization Report; World Health Organization: Geneva, Switzerland, 2022. [Google Scholar]
CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi, 3rd ed.; CLSI Standard M38; Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2017. [Google Scholar]
CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, 4th ed.; CLSI Standard M27; Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2017. [Google Scholar]
Denning, D.W.; Hanson, L.H.; Perlman, A.M.; Stevens, D.A. In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents. Diag. Micro. Infect. Dis. 1992, 15, 21–34. [Google Scholar] [CrossRef]
Giovati, L.; Ciociola, T.; Magliani, W.; Conti, S. Antimicrobial peptides with antiprotozoal activity: Current state and future perspectives. Future Med. Chem. 2018, 10, 2569–2572. [Google Scholar] [CrossRef]
Mishra, B.; Reiling, S.; Zarena, D.; Wang, G. Host defense antimicrobial peptides as antibiotics: Design and application strategies. Curr. Opin. Chem. Biol. 2017, 38, 87–96. [Google Scholar] [CrossRef]
Kuroda, K.; Caputo, G.A. Antimicrobial polymers as synthetic mimics of host defense peptides. WIREs Nanomed. Nanobiotechnol. 2013, 5, 49–66. [Google Scholar] [CrossRef]
Sierra, J.M.; Fusté, E.; Rabanal, F.; Vinuesa, T.; Viñas, M. An overview of antimicrobial peptides and the latest advances in their development. Expert Opin. Biol. Ther. 2017, 17, 663–676. [Google Scholar] [CrossRef]
Grigoreva, A.; Bardasheva, A.; Tupitsyna, A.; Amirkhanov, N.; Tikunova, N.; Pyshniyi, D.; Kleshev, M.; Ryabchikova, E. Changes in the ultrastructure of Candida albicans treated with cationic peptides. Microorganisms 2020, 8, 582. [Google Scholar] [CrossRef]
Lima, P.G.; Souza, P.F.N.; Freitas, C.D.T.; Oliveira, J.T.A.; Dias, L.P.; Neto, J.X.S.; Vasconcelos, I.M.; Lopes, J.L.S.; Sousa, D.O.B. Anticandidal activity of synthetic peptides: Mechanisms of action revealed by scanning electron and fluorescence microscopies and synergism effect with nystatin. J. Pep. Sci. 2020, 26, e3249. [Google Scholar] [CrossRef]
Delattin, N.; De Brucker, K.; De Cremer, K.; Cammue, B.P.A.; Thevissen, K. Antimicrobial peptides as a strategy to combat fungal biofilms. Curr. Top. Med. Chem. 2017, 17, 604–612. [Google Scholar] [CrossRef]
Sheehan, G.; Bergsson, G.; McElvaney, L.G.; Reeves, E.P.; Kavanagh, K. The human cathelicidin antimicrobial peptide LL-37 promotes the growth of the pulmonary pathogen Aspergillus fumigatus. Infect. Immun. 2018, 86, e00097-18. [Google Scholar] [CrossRef]
Hacioglu, M.; Guzel, C.B.; Savage, P.B.; Tan, A.S.B. Antifungal susceptibilities, in vitro production of virulence factors and activities of ceragenins against Candida spp. isolated from vulvovaginal candidiasis. Med. Mycol. 2019, 57, 291–299. [Google Scholar] [CrossRef]
Mercer, D.K.; Torres, M.D.T.; Duay, S.S.; Lovie, E.; Simpson, L.; von Kockritz-Blickwede, M.; de la Fuentes-Nunez, C.; O’Neil, D.A.; Angeles-Boza, A.M. Antimicrobial susceptibility testing of antimicrobial peptides to better predict efficacy. Front. Cell. Infect. Microbiol. 2020, 10, 326. [Google Scholar] [CrossRef]
dos Reis, T.F.; de Castro, P.A.; Bastos, R.W.; Pinzan, C.F.; Souza, P.F.N.; Ackloo, S.; Hossein, M.A.; Drewry, D.H.; Alkhazraji, S.; Ibrahim, A.S.; et al. A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi. Nat. Commun. 2023, 14, 2052. [Google Scholar] [CrossRef]
Corbett, D.; Wise, A.; Langley, T.; Skinner, K.; Trimby, E.; Birchall, S.; Dorall, A.; Sandiford, S.; Williams, J.; Warn, P.; et al. Potentiation of antibiotic activity by a novel cationic peptide: Potency and spectrum of activity of SPR741. Antimicrob. Agents Chemother. 2017, 61, e00200-17. [Google Scholar] [CrossRef]
Mensa, B.; Kim, Y.H.; Choi, S.; Scott, R.; Caputo, G.A.; DeGrado, W.F. Antibacterial mechanism of action of arylamide foldamers. Antimicrob. Agents Chemother. 2011, 55, 5043–5053. [Google Scholar] [CrossRef]
Stevens, D.A.; Moss, R.B.; Hernandez, C.; Clemons, K.V.; Martinez, M. Effect of media modified to mimic cystic fibrosis sputum on the susceptibility of Aspergillus fumigatus, and the frequency of resistance at one center. Antimicrob. Agents Chemother. 2016, 60, 2180–2184. [Google Scholar] [CrossRef] [PubMed]
Ferreira, J.A.G.; Penner, J.; Moss, R.B.; Haagensen, J.A.J.; Clemons, K.V.; Spormann, A.M.; Nazik, H.; Cohen, K.; Banaei, N.; Carolino, E.; et al. Inhibition of Aspergillus fumigatus and its biofilm by Pseudomonas aeruginosa is dependent on the source, phenotype and growth conditions of the bacterium. PLoS ONE 2015, 10, e0134692. [Google Scholar] [CrossRef]
Overhage, J.; Campisano, A.; Bains, M.; Torfs, E.C.; Rehm, B.H.; Hancock, R.E. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect. Immun. 2008, 76, 4176–4182. [Google Scholar] [CrossRef] [PubMed]
Ageitos, J.M.; Sánchez-Pérez, A.; Calo-Mata, P.; Villa, T.G. Antimicrobial peptides (AMPs): Ancient compounds that represent novel weapons in the fight against bacteria. Biochem. Pharmacol. 2017, 133, 117–138. [Google Scholar] [CrossRef] [PubMed]
Sahl, H.-G.; Pag, U.; Bonness, S.; Wagner, S.; Antcheva, N.; Tossi, A. Mammalian defensins: Structures and mechanism of antibiotic activity. J. Leukocyte Biol. 2005, 77, 466–475. [Google Scholar] [CrossRef] [PubMed]
Wu, J.; Liu, S.; Wang, H. Invasive fungi-derived defensins kill drug-resistant bacterial pathogens. Peptides 2018, 99, 82–91. [Google Scholar] [CrossRef] [PubMed]
Kratochvil, H.T.; Newberry, R.W.; Mensa, B.; Mravic, M.; DeGrado, W.F. Spiers Memorial Lecture: Analysis and de novo design of membrane-interactive peptides. Faraday Discuss. 2021, 24, 9–48. [Google Scholar] [CrossRef]
Tew, G.N.; Liu, D.; Chen, B.; Doerksen, R.J.; Kaplan, J.; Carroll, P.J.; Klein, M.L.; DeGrado, W.F. De novo design of biomimetic antimicrobial polymers. Proc. Nat. Acad. Sci. USA 2002, 99, 5110–5114. [Google Scholar] [CrossRef]
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MDPI and ACS Style
Larwood, D.J.; Stevens, D.A. Antifungal Activity of Brilacidin, a Nonpeptide Host Defense Molecule. Antibiotics 2024, 13, 405. https://doi.org/10.3390/antibiotics13050405
AMA Style
Larwood DJ, Stevens DA. Antifungal Activity of Brilacidin, a Nonpeptide Host Defense Molecule. Antibiotics. 2024; 13(5):405. https://doi.org/10.3390/antibiotics13050405
Chicago/Turabian Style
Larwood, David J., and David A. Stevens. 2024. "Antifungal Activity of Brilacidin, a Nonpeptide Host Defense Molecule" Antibiotics 13, no. 5: 405. https://doi.org/10.3390/antibiotics13050405
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Innovation Pharmaceuticals Inc. (IPIX)
$IPIX NEWS - http://ipharminc.com/press-release
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From the most recent 10-K:
There are doubts about our ability to continue as a going concern.
We have generated revenue of $0 and $18,000 for the fiscal years ended June 30, 2023 and 2022, respectively and have an accumulated deficit of $125.3 million through June 30, 2023. These factors raise substantial doubt about our ability to continue as a going concern.
We need to raise substantial additional capital in the future to fund our operations and we may be unable to raise such funds when needed and on acceptable terms, which could prevent us from fully implementing our business, operating and development plans.
We currently have an approximate $1.0 million cash balance as of the date of this filing, but that is insufficient to complete the development and commercialization of any of our proposed products. We expect to incur costs of approximately $1.8 million in the upcoming fiscal year ending June 30, 2024 to operate our business in accordance with our business plans and budgets.
We have limited experience in drug and formulation development, the conduct of clinical trials, and may not be able to successfully develop any drugs.
Development of pharmaceutical products is a risky and time-consuming process subject to a number of factors, many of which are outside of our control. We are subject to regulatory authority permissions and approvals, most importantly the FDA. Our drug candidate(s)/indications are at early and mid-stages of development. Consequently, we can provide no assurance of the successful and timely development of new drugs, and the failure to do so could cause us to cease operations.
We may elect to deregister our common stock under the Exchange Act and suspend our reporting obligations. Such deregistration and suspension would result in less disclosure about us and may negatively affect the liquidity and trading prices of our common stock.
http://www.ipharminc.com/
About Innovation Pharmaceuticals Inc.:
Established in 2007, and headquartered in Wakefield, Massachusetts, Innovation Pharmaceuticals Inc. (formerly Cellceutix Corporation) is a publicly traded biopharmaceutical company dedicated to discovering and advancing innovative medical therapies with dermatology, oncology, anti-inflammatory and antibiotic applications.
Through ongoing research and drug development efforts, Innovation is focused on improving the clinical care of patients, as well as growing shareholder value. Our team consists of a diverse and accomplished group of professionals working together toward achieving this common goal.
IPIX CEO - "The Company historically devoted most of its efforts and resources on business development, regulatory matters, and clinical trials. Presently, the Company does not have sufficient financial resources to advance our drug candidates meaningfully." "In general, we expect to concentrate on product development and engage in a limited way in product discovery, avoiding the significant investment of time and financial resources that is generally required for a promising compound to be identified and brought into clinical trials." Source - https://www.sec.gov/ix?doc=/Archives/edgar/data/1355250/000147793223003414/ipix_10q.htm
More information is available at http://www.ipharminc.com.
Management: http://www.ipharminc.com/senior-management/
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Trials under previous name: https://clinicaltrials.gov/ct2/results?cond=&term=cellceutix&cntry=&state=&city=&dist=&Search=Search&flds=abcefgps
Product Pipeline: http://www.ipharminc.com/therapeutic-areas/
Recent News and Press Releases:
https://finance.yahoo.com/quote/IPIX?p=IPIX
http://www.ipharminc.com/press-release/
SEC Filings (CIK:0001355250): https://www.sec.gov/cgi-bin/browse-edgar?company=Innovation+Pharmaceutical&owner=exclude&action=getcompany
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