Infections caused by opportunistic fungi, namely Candida species, have gained significant attention in the last few decades. Such infections are not uncommon but present elevated mortality rates, particularly in immune-compromised patients. Nowadays, a limited number of antifungal drugs are available for treating such infections and are also often related to severe adverse effects. Therefore, new drugs and innovative technologies for treating this infection are necessary (1).
Antibody therapeutics was revolutionized by discovering a method to generate Monoclonal antibodies (mAbs) by immortalizing B cells in 1975, which was developed into Hybridoma technology (2). In the last decades of the twentieth century, there were several new technological advances, including creating transgenic mice that produce only human antibodies (3), direct cloning of variable genes into phage expression libraries (4), and the immortalization of human peripheral cells. Together, these technologies aid in producing monoclonal antibodies against almost any antigen, even though each technology has innated limitations.
Passive antibody therapy has been used against many microorganisms responsible for human disease, including representatives of the viral, bacterial, fungal, and parasitic microbial groups. Whether a Fab fragment or intact antibody is suitable as a therapeutic agent also depends on the microorganism being targeted and the immunological status of the host. As biological effects that rely on the Fc receptor could require intact host immunological function, antibodies that have direct antimicrobial effects or mediate beneficial effects by the binding of Fab alone might be more useful in immune-compromised hosts. Antibodies with direct antimicrobial properties have recently been described against several microorganisms, including Borrelia spp. (5), Candida albicans (6, 7), and Cryptococcus neoformans (8).
In addition, recent studies suggest that combinations of antibodies and drugs are more effective against fungal infections than when either therapy is used alone (6, 9, 10).
In addition to their advantages as therapeutic agents, antibodies have had a central role in vaccine development. Historically, vaccine development for numerous infectious diseases was fueled by antibody-based therapies and research into antibody-mediated immunity. Antibody therapy can be protective against infectious disease, suggesting that a vaccine that elicits similar antibodies could protect against the relevant pathogen. More recently, the generation of protective mAbs against C. neoformans and C. Albicans identified polysaccharide antigens used to design effective conjugate vaccines (11, 12).
New directions in anti-infective antibody therapy
Analysis of the susceptibility of fungal cells to radiolabeled mAbs that bind to surface antigens in vitro, using both C. neoformans and H. capsulatum, showed markedly greater susceptibility to killing by antibody-delivered particulate (β- and α-particles) radiation than to external γ-radiation (13). Even though this is not well understood, particulate radiation delivered near microbial cells may have greater killing power than γ-photons. Alternatively, antibody effects, such as the recently described ability to generate oxygen-related oxidants (14), might synergistically increase the killing power of locally emitted radiation.
Identifying new antifungal target-specific therapeutic strategies and developing novel compound scaffolds to eradicate established biofilms and inhibit biofilm formation are practical approaches to combat infectious diseases.
New Synthetic Drug Isolates
Small molecules are a valuable and promising source of new antifungal agents. Capable of inhibiting the transition from yeast to hyphae in C. Albicans, the small molecule 21 (SM21) is a potent inhibitor of this conversion at low concentrations (15).
The patent “CN105102441 (A)” (16) intervention reports the use of new compounds and their derivatives to treat fungal infections. The SM21 compound exhibits antifungal activity against a wide range of fungal species, inhibiting the conversion of yeast to hypha, improving antifungal activity against fungi isolates drug-resistance, and exhibiting potent anti-biofilm activity against fungal biofilms that are resistant to the antifungal agents currently available.
The pharmaceutical compound form can be a solution, suspension, gel, liquid gel, emulsion, emulsion gel, lotion, ointment, film-forming solution, creams, and sprays. Also disclosed in the same patent content, there is a medical device with a surface, where at least a portion of this surface includes a coating compound. The SM21 compound anti-biofilm activity was evaluated against Candida biofilm and mixed biofilm species by determining the minimum inhibitory concentration (MIC) exhibits. In vivo tests with mice exhibiting systemic candidiasis have also confirmed antifungal activity and deemed it safe (16).
The Chinese patent applications “CN108836976 (A)” (16),” CN108743575 (A)” (16),” CN108578400 (A)” (16), and “CN108524491 (A)” (16) describe the application of ginsenoside RG5, butyl p-hydroxybenzoate, chrysanthemum, and hydroxycopaine, respectively, in the preparation of an anti-C. albicans drug. The detection of the activity of these compounds was tested against standard strains of C. Albicans using both virulence and cytotoxicity tests, as well as employing cell culture to evaluate the effect of these compounds on C. Albicans growth adhesion and biofilm formation. The results were positive for all tests, showing that the compounds act upon the adhesion of C. Albicans and the formation of biofilms and the pathogenicity of the fungus.
Another patent, “US2019015385 (A1)” (17), reports the use of a vitamin E phosphate, which can be combined with methylene blue and/or vitamin E acetate, in combination with methylene blue for the treatment and prevention of biofilm infections or as an antifungal mediator. The formulation can be applied or combined with a biocompatible vector on inert or living surfaces (17). Several studies have already shown that the use of vitamin E can prevent fungal biofilm by reducing fungal adherence to a biomaterial and minimizing biomedical device oxidation (18).
Association of antifungals substances and drugs
The association of antifungal substances and drugs is disclosed in the” WO2014124504 (A1)” (16) patent. This patent publication presents new methods and compositions for the treatment or prevention of microbial biofilms, preferably fungal biofilms formed on medical devices. More particularly, these methods and compositions are comprised of a combination of an antifungal agent with a potentiating compound (perhexiline, drospirenone, and toremifene). The mechanism of action of these compounds is supposed to increase the antibiofilm activity of the antifungal agent and reduce, eradicate, inhibit, or prevent biofilm formation on the medical device’s surface or another medium susceptible to biofilm formation. The three compounds previously mentioned were evaluated for potentiation and synergism with currently used drugs, such as amphotericin B and caspofungin, against C. Albicans and Candida glabrata biofilms (16). Synergistic activity against C. Albicans and C. glabrata biofilms, using drospirenone, perhexiline, and toremifene combined with caspofungin, confirmed by checkerboard analysis. Additionally, the combination of antifungal agents with potentiating compounds has been reported to reduce the standard caspofungin concentration to inhibit biofilm formation, up to 20-fold, as well as to decrease the activity of C. Albicans or C. glabrata to at least 50 percent (19).
Association of antifungal and natural products
Farnesol is a natural compound found in essential oils of several plants (such as Brazilian sandalwood, okra, acacia, jasmine, and orange blossom) and on an extracellular chemical molecule secreted by C. Albicans. Studies suggest that exogenous farnesol tested on a strain of C. Albicans, which does not produce endogenous farnesol, suppresses hyphae formation, thus inducing morphological changes on the wall of yeast cells. Other claims include biofilm cell dispersion, development of mature architecture, cell adhesion to substrates, and prevention of C. Albicans biofilms (16, 20).
Another patent, “CN107625755 (A)” (16), provides an antifungal drug combined with farnesol or methods to inhibit Candida biofilms. Studies have confirmed that it can increase Candida susceptibility to the antifungals: fluconazole, 5-fluorouracil, nystatin, amphotericin B, caspofungin, and itraconazole compounds. Farnesol itself has a certain antifungal effect; however, it substantially inhibits the formation and growth of C. Albicans biofilm when combined with antifungal drugs. The antifungal composition can be used in external disinfection of prostheses and devices and the treatment of local oral infections.
Another recently developed patent,” CN106511420 (A)” (16), refers to the application of cynanche root, specifically the use of the Baiwei substance, in the preparation of an antifungal composition alone or combined with antifungal drugs already in use. The antimicrobial effects of Baiwei are observed in saponin compounds, which have an inhibitory effect on pneumococcus bacteria and present good inhibitory effects on fungi. Therefore, when combined with antifungal drugs, Baiwei can significantly reduce the dose of conventional drugs, improve its antimicrobial inhibitory effects, and restore and increase the effects of antifungals applied to drug-resistant fungi. These antifungal drugs include the use of fluconazole, ketoconazole, voriconazole, or amphotericin B, to suppress the activity of C. Albicans, C. parapsilosis, C. glabrata, C. neoformans, Microsporum gipsita, and Trichophyton rubrum fungi.
Isolated Natural products:
A variety of molecules are derived from natural plants, herbal extracts, including lichen extracts (Parmeliaceae and Cladoniaceae), grapefruit seeds, red raspberry, and the underlying mechanisms of antibiofilm activities have also been investigated (21-25). Another isolated natural extract used in antifungal formations is chelerythrine, an extract, which is an alkaloid present in plants like Bo Luohu. In vitro experiments have proven that chelerythrine extract has good fungal anti-biofilm activity, effectively inhibiting the growth and proliferation of biofilms and mature biofilms even at low concentrations.
Methods, apparatus, and systems
Seneviratne et al. (26) reviewed the patenting and technological trends in hernia implants, stated that the most severe complication after implantation of a biomedical device is microbial infection and biofilm formation. Incorporation of antibacterial and antifungal agents and biomaterial surface modifications such as including anti-adhesion coating layers were reported among the methods to reduce and prevent microbial implant infections (26).
Chávez-Andrade et al. (27), reviewing biomedical devices prepared with antifungal agent surface coatings, focused on the need to address, and understand specific biomaterial surface modifications that have significant effects on the fungal mechanisms of action. However, implant‐related biofilm infections typically show recurrence. If not safely eradicated from medical devices, bacteria and fungi can acquire resistance leading to chronic device-related infections and the removal of the medical device even after traditional antifungal or antibacterial drug therapy. In recent years, increased attention has been given to the development of novel alternatives to eradicate biofilms from biomedical devices, including implant surface physicochemical modifications and the use of phototherapeutic systems (28).
Increased attention has also been given to the use of silver nanoparticles in combination with synthetic and natural polymers, including the elastomer polymer rubber, owing to its physicochemical, biological, as well as antifungal, and anti-inflammatory properties (29, 30). It has been reported that sub-inhibitory concentrations of metal ions can induce changes in the structure of C. albicans and C. tropicalis biofilms by blocking and regulating yeast progression to hyphal transition (31). It is believed that a synergistic effect is obtained using inorganic metals such as silver, which tends to exhibit controlled slow release of the antibacterial agent, and organic compounds such as zinc pyrithione, which tends to exhibit the quickest release of active antimicrobial compounds.
It is an exciting time for technological developments in the healthcare field, specifically regarding advancements that will help with yeast infection prevention. As yeast infections are very common among the large population, these technological innovations will be a game-changer for both prevention aid and reduced mortality rates.
About the author:
Dan Jackowiak, Nc, HHP, Founder of Yeast Infection Advisor. Dan is a Holistic Healthcare Practitioner and Nutritional Consultant that personally suffered from yeast and bad bacterial overgrowth of the gut for most of his life. The information on his website is a combination of his own nutrition and holistic training, life experiences, collaboration with fellow experts on his team, and over 18 years of studying medical research on candida yeasts infections of all types, which has allowed him to take his life and health back help others overcome yeast-related health problems and digestive problems of all kinds.
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Susceptibility of the Human Pathogenic Fungi Cryptococcus neoformans and Histoplasma capsulatum to γ-Radiation Versus Radioimmunotherapy with α- and β-Emitting Radioisotopes | Journal of Nuclear Medicine (snmjournals.org)
Highly Effective and Noninvasive Near‐Infrared Eradication of a Staphylococcus aureus Biofilm on Implants by a Photoresponsive Coating within 20 Min – Li – 2019 – Advanced Science – Wiley Online Library