Antifungal therapy of Candida biofilms: Past, present and future

May combine two claims.

Virtually all Candida species linked to clinical candidiasis are capable of forming highly resistant biofilms on different types of surfaces, which complicates therapy of these infections.

“Virtually all Candida species linked to clinical candidiasis are capable of forming highly resistant biofilms on different types of surfaces, which poses an additional significant threat and further complicates therapy of these infections.”

• cites [5] Silva, 2012, Candida glabrata, Candida parapsilosis and Candida tropicalis: biology, epidemiology, pathogenicity and antifungal resistance, FEMS Microbiol Rev sourceNot checked yet

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• cites [8] Cuellar-Cruz, 2012, Candida species: new insights into biofilm formation, Future Microbiol sourceNot checked yet

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• cites [9] Wall, 2019, Candida albicans biofilm growth and dispersal: contributions to pathogenesis, Curr Opin Microbiol sourceNot checked yet

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May combine two claims.

There is a scarcity of antifungal agents, and their effectiveness, particularly against biofilms, is limited.

“There is a scarcity of antifungal agents, and their effectiveness, particularly against biofilms, is limited.”

• cites [21,[23], [24], [25]]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Azole derivatives were developed mostly in the 1980s and 1990s and represent the largest class of antifungal agents used today in clinical medicine.

“Azole derivatives was the next class of antifungals, developed mostly in the 1980s and 1990s [23,24]. They represent the largest class of antifungal agents used today in clinical medicine [35].”

• cites [23] Odds, 2003, Antifungal agents: mechanisms of action, Trends Microbiol sourceNot checked yet

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• cites [24] Ostrosky-Zeichner, 2010, An insight into the antifungal pipeline: selected new molecules and beyond, Nat Rev Drug Discov sourceNot checked yet

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• cites [35] Perfect, 2017, The antifungal pipeline: a reality check, Nat Rev Drug Discov sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Drug discovery and development is arduous, failure-prone, time-consuming and very costly, taking up to 20 years and 2 billion dollars.

“Drug discovery and development represents an arduous, failure-prone, time-consuming and very costly proposition; up to 20 years and 2 billion dollars [49].”

• cites [49] Rennane, 2021, Estimating the cost of industry investment in drug research and development: a review of methods and results, InquiryNot checked yet

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May combine two claims.

Azoles target ergosterol by inhibiting its biosynthetic pathway, specifically cytochrome P-450 14-alpha lanosterol demethylase, and are considered fungistatic.

“Azoles also target ergosterol, but by inhibiting its biosynthetic pathway, most specifically the cytochrome P-450 14-alpha lanosterol demethylase, and they are considered fungistatic drugs [23,25].”

• cites [23] Odds, 2003, Antifungal agents: mechanisms of action, Trends Microbiol sourceNot checked yet

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• cites [25] Wall, 2020, Current antimycotics, new prospects, and future approaches to antifungal therapy, Antibiotics (Basel)Not checked yet

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May combine two claims.

Candida cells within biofilms are protected from a variety of environmental stresses, including host defenses and antifungal treatment, and biofilm development contributes greatly to the pathogenesis of candidiasis and complicates treatment.

“Furthermore, Candida cells within these highly organized structures are protected from a variety of environmental stresses, including host defenses and antifungal treatment, and as such biofilm development contributes greatly to the pathogenesis of candidiasis and greatly complicates treatment for these patients [5,9].”

• cites [5] Silva, 2012, Candida glabrata, Candida parapsilosis and Candida tropicalis: biology, epidemiology, pathogenicity and antifungal resistance, FEMS Microbiol Rev sourceNot checked yet

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• cites [9] Wall, 2019, Candida albicans biofilm growth and dispersal: contributions to pathogenesis, Curr Opin Microbiol sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ibrexafungerp was approved for treatment of vulvovaginal candidiasis in 2021, representing the first approved drug within a novel antifungal class in more than 20 years.

“Ibrexafungerp was recently approved for the treatment of vulvovaginal candidiasis in 2021, and as such represents the first approved drug within a novel antifungal class in more than 20 years.”

May combine two claims.

Rezafungin is a new long-acting echinocandin with improved stability and extended half-life compared to first-generation echinocandins, potentially allowing once-a-week dosing.

“Rezafungin (formerly CD101) is a new long-acting echinocandin with improved stability and extended half life as compared to the first generation drugs within this class, thereby potentially allowing for once a week dosing [41].”

• cites [41] Zhao, 2016, CD101: a novel long-acting echinocandin, Cell Microbiol sourceNot checked yet

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May combine two claims.

At present there are a handful of investigational agents at different stages of the antifungal development pipeline; the majority target ergosterol or 1,3-β-D-glucan, but some novel classes with novel targets and mechanisms are included.

“At the present time there are a handful of investigational agents at different stages of the antifungal development pipeline. Although the majority still target ergosterol (same as azoles) or 1,3-β-D-glucan (same as echinocandins), they also include some novel classes with novel targets and mechanisms [25,39,40].”

• cites [25] Wall, 2020, Current antimycotics, new prospects, and future approaches to antifungal therapy, Antibiotics (Basel)Not checked yet

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• cites [39] Hoenigl, 2021, The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin, Drugs sourceNot checked yet

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• cites [40] Wiederhold, 2018, The antifungal arsenal: alternative drugs and future targets, Int J Antimicrob Agents sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Polyenes, azoles and echinocandins are the main classes of existing antifungal agents used for the treatment of Candida infections.

“Polyenes, azoles and echinocandins are the main classes of existing antifungal agents used for the treatment of Candida infections [[23], [24], [25]].”

• cites [[23], [24], [25]]Not checked yet

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May combine two claims.

Newer liposomal formulations of amphotericin B showed unique activity against Candida biofilms, which can be attributed to better penetration across the biofilm matrix.

“Nevertheless, the Ghannoum group demonstrated that newer liposomal formulations of amphotericin B showed unique activity against Candida biofilms [34], which can be attributed to better penetration of these formulation across the biofilm matrix.”

• cites [34] Kuhn, 2004, Candida biofilms: antifungal resistance and emerging therapeutic options, Curr Opin Invest DrugsNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Echinocandins were first discovered in the 1970s, developed mostly during the 1990s, and caspofungin, the first FDA-approved member, entered the market in the early 2000s.

“Echinocandins, the newest class of antifungals, were first discovered in the 1970s, although their development took place mostly during the 1990s, and it was not until the early 2000s when caspofungin, the first FDA-approved member of this class, entered the market [25,30,31].”

• cites [25] Wall, 2020, Current antimycotics, new prospects, and future approaches to antifungal therapy, Antibiotics (Basel)Not checked yet

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• cites [30] Denning, 2002, Echinocandins: a new class of antifungal, J Antimicrob Chemother sourceNot checked yet

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• cites [31] Johnson, 2003, Caspofungin: first approved agent in a new class of antifungals, Expet Opin Pharmacother sourceNot checked yet

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May combine two claims.

Exacerbated biofilm tolerance complicates the management of biofilm-associated Candida infections considerably and contributes to therapeutic failure.

“This exacerbated biofilm tolerance complicates the management of biofilm-associated Candida infections considerably and contributes to therapeutic failure.”

May combine two claims.

Ibrexafungerp is a new semi-synthetic terpenoid drug targeting 1,3-β-D-glucan synthase, structurally different from echinocandins.

“Also targeting 1,3-β-D-glucan synthase but structurally different to the echinocandins, Ibrexafungerp (formerly SCY-078, formerly MK-3118) is a new semi-synthetic terpenoid drug, currently being developed by Scynexis Inc [43].”

• cites [43] Jallow, 2021, Ibrexafungerp: a first-in-class oral triterpenoid glucan synthase inhibitor, J Fungi (Basel).Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The anti-biofilm activity of tetrazoles against Candida spp. has not been exhaustively tested.

“To our knowledge, their anti-biofilm activity against Candida spp. has not been exhaustively tested.”

May combine two claims.

Tetrazoles VT-1129, VT-1161, and VT-1598 target 14-alpha-lanosterol demethylase, same as azoles, but display increased selectivity for the fungal enzyme over mammalian cytochrome p-450 enzymes.

“Their molecular target is the same as for the azoles, 14-alpha-lanosterol demethylase [48], but these tetrazoles display increased selectivity for the fungal enzyme over mammalian cytochrome p-450 enzymes [48].”

• cites [48] Warrilow, 2016, The investigational drug VT-1129 is a highly potent inhibitor of cryptococcus species CYP51 but only weakly inhibits the human enzyme, Antimicrob Agents Chemother sourceNot checked yet

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May combine two claims.

Early work in the late 1990s and early 2000s demonstrated potent antifungal activity of physiological concentrations of echinocandins against C. albicans biofilms, with subsequent studies extended to other Candida spp.

“Early work in these academic laboratories in the late 1990s and early 2000s demonstrated the potent antifungal activity of physiological concentrations of echinocandins against C. albicans biofilms, with subsequent studies extended to other Candida spp [34,37,38].”

• cites [34] Kuhn, 2004, Candida biofilms: antifungal resistance and emerging therapeutic options, Curr Opin Invest DrugsNot checked yet

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• cites [37] Bachmann, 2002, In vitro activity of caspofungin against Candida albicans biofilms, Antimicrob Agents Chemother sourceNot checked yet

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• cites [38] Marcos-Zambrano, 2016, Biofilm production and antibiofilm activity of echinocandins and liposomal amphotericin B in echinocandin-resistant yeast species, Antimicrob Agents Chemother sourceNot checked yet

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May combine two claims.

Fosmanogepix inhibits inositol acyltransferase Gwt1, preventing GPI-anchored protein maturation, a process critical for linkages between fungal cell wall components.

“Fosmanogepix inhibits the inositol acyltransferase Gwt1 which catalyzes and early step in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway, thereby preventing GPI-anchored protein maturation, a process critical for linkages between different components of the fungal cell wall [39,46].”

• cites [39] Hoenigl, 2021, The antifungal pipeline: fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin, Drugs sourceNot checked yet

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• cites [46] Berkow, 2018, Activity of novel antifungal compound APX001A against a large collection of Candida auris, J Antimicrob Chemother sourceNot checked yet

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May combine two claims.

Polyene efficacy is severely compromised by intrinsic toxicity, particularly nephrotoxicity, and infusion-related toxicity.

“However, their efficacy is severely compromised by their intrinsic toxicity, particularly nephrotoxicity, and also by infusion-related toxicity [23].”

• cites [23] Odds, 2003, Antifungal agents: mechanisms of action, Trends Microbiol sourceNot checked yet

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May combine two claims.

Candida biofilms afford fungal cells a safe haven, constitute reservoirs for persistent sources of candidiasis, and can negatively affect the function of implanted devices.

“In addition, Candida biofilms afford fungal cells a safe haven, constitute reservoirs for persistent sources of candidiasis, and can also negatively affect the function of implanted devices [29].”

• cites [29] Ramage, 2006, Candida biofilms on implanted biomaterials: a clinically significant problem, FEMS Yeast Res sourceNot checked yet

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May combine two claims.

Screening of chemical libraries identified diazaspiro-decane structural analogs (Pierce et al.) and compounds with a biaryl amide core (Romo et al.) as inhibitors of C. albicans biofilm formation.

“Pierce et al. reported on the identification of a new series of diazaspiro-decane structural analogs which were largely represented among the bioactive compounds [51]; whereas as reported in Romo et al. the two main hits belonged to a novel series of bioactive compounds with a common biaryl amide core structure [[52], [53], [54]].”

• cites [51] Pierce, 2015, A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance, NPJ Biofilms Microbiomes sourceNot checked yet

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• cites [[52], [53], [54]]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Echinocandins are semisynthetic lipopeptide antibiotics that inhibit 1,3-β-D-glucan synthase, the key enzyme for synthesis of glucan, the main structural component of the Candida cell wall.

“These drugs are a group of semisynthetic lipopeptide antibiotics which inhibit 1,3-β-D-glucan synthase, the key enzyme for the synthesis of glucan, the main structural component of the Candida cell wall [30].”

• cites [30] Denning, 2002, Echinocandins: a new class of antifungal, J Antimicrob Chemother sourceNot checked yet

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May combine two claims.

The antifungal arsenal is exceedingly short, mostly due to the paucity of selective targets for antifungal drug development because of the close relatedness of human and fungal cells.

“the antifungal arsenal is exceedingly short, mostly a consequence of the paucity of selective targets for antifungal drug development due to the close relatedness of human and fungal cells [21,[23], [24], [25]]”

• cites [21,[23], [24], [25]]Not checked yet

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May combine two claims.

Echinocandins display potent fungicidal activity against the majority of Candida species and have an excellent safety profile, contributing to them becoming front-line therapy for candidiasis.

“Agents within this class display potent fungicidal activity against the majority of species within the Candida genus, which added to their excellent safety profile (the cell was is fungal specific and not present in mammalian cells), contributed to echinocandins becoming front-line therapy for the treatment of candidiasis [30].”

• cites [30] Denning, 2002, Echinocandins: a new class of antifungal, J Antimicrob Chemother sourceNot checked yet

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May combine two claims.

Polyenes are the oldest class of antifungal agents, dating back to the 1950s, with amphotericin B being the first FDA-approved antifungal for invasive fungal infections including candidiasis.

“The polyenes are the oldest class of antifungal agents, their discovery and development dating back to the 1950s, with amphotericin B being the first ever FDA-approved antifungal for the treatment of invasive fungal infections, including candidiasis [23,24].”

• cites [23] Odds, 2003, Antifungal agents: mechanisms of action, Trends Microbiol sourceNot checked yet

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• cites [24] Ostrosky-Zeichner, 2010, An insight into the antifungal pipeline: selected new molecules and beyond, Nat Rev Drug Discov sourceNot checked yet

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May combine two claims.

Amphotericin B was approximately 10 times less potent under biofilm versus planktonic growing conditions, but the high concentrations needed to effectively kill biofilms are considered toxic and unsafe, restricting its use.

“For example, amphotericin B was approximately 10 times less potent when tested under biofilm-versus planktonic-growing conditions, but these high concentrations needed to effectively kill biofilms are considered toxic and unsafe, effectively restricting its use [22].”

• cites [22] Ramage, 2001, Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms, Antimicrob Agents Chemother sourceNot checked yet

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May combine two claims.

Rezafungin is active against C. albicans biofilms, inhibiting biofilm formation and being effective against mature biofilms.

“Consistent with previous studies of echinocandins, rezafungin is also active against C. albicans biofilms, as treatment with this drug both inhibits biofilm formation and is affective against mature biofilms [42].”

• cites [42] Chandra, 2018, CD101, a novel echinocandin, possesses potent antibiofilm activity against early and mature Candida albicans biofilms, Antimicrob Agents Chemother sourceNot checked yet

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May combine two claims.

The repurposing pathway is significantly faster, cheaper, and more likely to succeed compared to de novo drug discovery.

“This makes the repurposing pathway significantly faster, cheaper, and more likely to succeed as compared to “de novo” drug discovery that searches for entirely new chemical matter.”

May combine two claims.

Initial experiments demonstrated increased activity of AgNPs against C. albicans, including preformed biofilms, and most recently this research has expanded to other Candida spp., particularly C. auris.

“While initial experiments demonstrated the increased activity of AgNPs against C. albicans, including preformed biofilms [76,77], most recently this research has also expanded to other Candida spp., and in particular C. auris [78,79].”

• cites [76] Lara, 2015, Effect of silver nanoparticles on Candida albicans biofilms: an ultrastructural study, J Nanobiotechnol sourceNot checked yet

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• cites [77] Monteiro, 2011, Silver colloidal nanoparticles: antifungal effect against adhered cells and biofilms of Candida albicans and Candida glabrata, Biofouling sourceNot checked yet

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• cites [78] Lara, 2020, Inhibition of Candida auris biofilm formation on medical and environmental surfaces by silver nanoparticles, ACS Appl Mater Interfaces sourceNot checked yet

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• cites [79] Vazquez-Munoz, 2020, Silver nanoantibiotics display strong antifungal activity against the emergent multidrug-resistant yeast Candida auris under both planktonic and biofilm growing conditions, Front Microbiol sourceNot checked yet

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May combine two claims.

Other approaches under investigation for Candida biofilms include antimicrobial peptides, inhibitors of biofilm matrix components (e.g., extracellular DNA), probiotics, hsp90 inhibition, modulators of quorum sensing, photodynamic therapy, catheter locks, surface coatings, and inhibition of biofilm dispersal.

“These include the use antimicrobial peptides, inhibitors of other components within the biofilm matrix (i.e. extracellular DNA), the use of probiotics, hsp90 inhibition, as well as modulators of quorum sensing [[87], [88], [89], [90], [91], [92], [93]]. An interesting methodology being developed and applied to the Candida biofilm field is that of photodynamic therapy (PDT), where the inhibitory”

• cites [[87], [88], [89], [90], [91], [92], [93]]Not checked yet

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• cites [[94], [95], [96], [97]]Not checked yet

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• cites [98] Cateau, 2008, In vitro efficacies of caspofungin or micafungin catheter lock solutions on Candida albicans biofilm growth, J Antimicrob Chemother sourceNot checked yet

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• cites [99] Bouza, 2014, The role of antifungals against Candida biofilm in catheter-related candidemia, Antibiotics (Basel) sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

There are significant shortcomings associated with the management of Candida infections with a biofilm etiology.

“There are significant shortcomings associated with the management of Candida infections with a biofilm etiology.”

May combine two claims.

Turbinmicin treatment nearly completely abrogated production of biofilm vesicles and was active against other Candida spp, including C. tropicalis, C. glabrata, and C. auris.

“Some very elegant follow-up studies demonstrated that turbinmicin treatment nearly completely abrogated the production of biofilm vesicles and that this new molecule was also active against other Candida spp, including C. tropicalis, C. glabrata, and C. auris [58].”

• cites [58] Zhao, 2021, Turbinmicin inhibits Candida biofilm growth by disrupting fungal vesicle-mediated trafficking, J Clin Invest sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

The lack of effective antifungal therapeutics greatly contributes to the excess morbidity and mortality rates associated with biofilm-associated candidiasis.

“Notably, the lack of effective antifungal therapeutics greatly contributes to the excess morbidity and mortality rates associated with biofilm-associated candidiasis.”

May combine two claims.

The synthesis and anti-Candida biofilm activity of bismuth metallic nanoparticles has been reported.

“The synthesis and anti-Candida biofilm activity of bismuth metallic nanoparticles has also been recently reported [[81], [82], [83]].”

• cites [[81], [82], [83]]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

One of the current major impediments of the use of nanoparticles is their limitations for systemic therapy.

“Of course, one of the current major impediments of the use of nanoparticles is their limitations for systemic therapy.”

May combine two claims.

Leading candidate repositionable drugs are already approved or have been through several stages of clinical development, so their pharmacological properties and safety in humans are already established.

“One of the distinct advantages of repurposing is the fact that the leading candidate repositionable drugs are already approved or at the very least have been through several stages of clinical development, and therefore the pharmacological properties of these drugs, and their safety in humans are already established [63,64].”

• cites [63] Ashburn, 2004, Drug repositioning: identifying and developing new uses for existing drugs, Nat Rev Drug Discov sourceNot checked yet

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• cites [64] Oprea, 2012, Drug repurposing: far beyond new targets for old drugs, AAPS J sourceNot checked yet

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May combine two claims.

Enterococcus faecalis can inhibit C. albicans morphogenesis, biofilm formation, and overall virulence.

“This is exemplified by a series of articles in the last few years by the Lorenz and Garsin groups, who initially reported on the interactions between Enterococcus faecalis and C. albicans, whereby the bacterium can inhibit C. albicans morphogenesis, biofilm formation, and overall virulence [59].”

• cites [59] Cruz, 2013, Enterococcus faecalis inhibits hyphal morphogenesis and virulence of Candida albicans, Infect Immun sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Lessons from the past and increasing understanding of Candida biofilms offer new opportunities for development of novel therapeutics to combat the threat of these infections.

“Lessons from the past and our increasing understanding of Candida biofilms offer new opportunities for the development of novel therapeutics to combat the threat that these devastating infections pose to an increasing number of at-risk patients.”

May combine two claims.

The active form of EntV is 68 amino acids, does not exhibit antifungal activity per se, and inhibits C. albicans biofilm formation both in vitro and in vivo.

“The active form of EntV is 68 amino acids [60], which per se does not exhibit antifungal activity, inhibits C. albicans biofilm formation both in vitro and in vivo [61].”

• cites [60] Brown, 2019, Antifungal activity of the Enterococcus faecalis peptide EntV requires protease cleavage and disulfide bond formation, mBio sourceNot checked yet

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• cites [61] Graham, 2017, Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans, Proc Natl Acad Sci U S A sourceNot checked yet

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May combine two claims.

The inhibitory activity of a variety of nanomaterials against Candida biofilms has been evaluated during approximately the last 10-15 years, with the majority of research on metal nanoparticles, more specifically silver nanoparticles.

“The inhibitory activity of a variety of nanomaterials against Candida biofilms has been evaluated during approximately the last 10–15 years, with the majority of research being on metal nanoparticles, and more specifically silver nanoparticles (AgNPs), synthesized by different methods.”

• cites [75] Li, 2021, Recent developments on using nanomaterials to combat Candida albicans, Front Chem sourceNot checked yet

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May combine two claims.

Turbinmicin inhibits the vesicle-delivered biofilm matrix, negating the protection that the biofilm matrix affords to C. albicans biofilms.

“The authors hypothesized and subsequently demonstrated that this new antifungal inhibited the vesicle-delivered biofilm matrix, thereby effectively negating the protection that the biofilm matrix affords to C. albicans biofilms, since many of the Candida biofilm matrix components are delivered by extracellular vesicles and this process is critical for drug resistance/tolerance [58].”

• cites [58] Zhao, 2021, Turbinmicin inhibits Candida biofilm growth by disrupting fungal vesicle-mediated trafficking, J Clin Invest sourceNot checked yet

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May combine two claims.

These biofilm inhibitors behave as true anti-virulence compounds and provide proof of concept for anti-virulence approaches against C. albicans.

“Altogether these biofilm inhibitors, with novel chemical structures and mode of action (inhibition of biofilm formation), behave as true anti-virulence compounds; and these studies provide proof of concept for the future implementation of anti-virulence approaches against C. albicans (and potentially other fungal infections) which would be less likely to foster the development of resistance.”

May combine two claims.

Both leading compounds were effective in vivo in murine models of hematogenously disseminated and oral candidiasis.

“both compounds were effective in vivo in the murine models of hematogenously disseminated and oral candidiasis [[51], [52], [53], [54]].”

• cites [[51], [52], [53], [54]]Not checked yet

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May combine two claims.

AgNPs can accumulate outside the Candida cell surface, interact with cell wall components and release ionic silver leading to cell death.

“AgNPs can also accumulate outside the Candida cell surface, interact with cell wall components and in the process release ionic silver leading to cell death [80].”

• cites [80] Vazquez-Munoz, 2014, Ultrastructural analysis of Candida albicans when exposed to silver nanoparticles, PLoS One sourceNot checked yet

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