Biofilm formation is an important factor of Candida pathogenesis with several clinical
implications. Most Candida spp. form biofilms on mucosal and skin surfaces causing
different types of superficial candidiasis, as well as on implanted medical devices
leading to systemic infections (Horton et al., 2020; Fan et al., 2022). The inherent
biofilm resistance to available antifungal drugs results in recurrent infections,
chronic persistent infections, and poor clinical outcomes (Ponde et al., 2021). The
Research Topic on “Candida biofilms” includes a collection of 14 original research
articles and three reviews prepared by renowned groups from Brazil, China, Germany,
India, Portugal, Spain, United Kingdom, and USA. Taken together the articles in this
issue give an overview on the field of Candida biofilms and provide insights on their
structure and regulatory networks; interactions with the host immune defense; mechanisms
involved in antifungal resistance; pathogenicity and clinical relevance; cross-kingdom
interactions; and development of novel therapeutic approaches.
In this context, Böttcher et al. present a detailed study about biofilm formation
of C. albicans with focus on the role of STP2, a key transcriptional regulator of
extracellular amino acid signaling and metabolism. The results demonstrate that STP2
mediates the adherence, germ tube formation, metabolic adaptation, and biofilm sustainability,
suggesting that regulatory responses to extracellular amino acids are not only involved
with nutritional homeostasis, but also coordinate crucial factors for biofilm development.
Related to this work, Wang et al. explore the complex mechanism of C. albicans to
respond to environmental challenges, unveiling that SPT20 plays an important role
to resist hyperosmotic stress through regulating the high osmolarity glycerol 1 mitogen
activated protein kinase transduction pathway (Hog1-MAPK). Moving focus to biofilms
formed by Candida glabrata, Santos et al. demonstrate that Drug:H+ antiporter 1 (DHA1)
transporters, involved in the activation of efflux pumps and drug resistance, can
also influence the biofilm development by affecting nutrient uptake and cellular adhesion.
Taken together, these studies contribute to clarify the intertwined network of pathways
involved in biofilms formed by Candida spp., making them promising targets for drug
development.
Looking into the influence of biofilms on Candida-host interactions and the role of
biofilm in Candida pathogenesis, Eix and Nett bring a comprehensive review on innate
immune responses associated with biofilms, highlighting the key mechanisms by which
Candida cells increase their resistance to phagocytosis and alter the mononuclear
cell cytokine profile. The authors also examine the insights into host responses to
biofilm provided by animal studies, and discuss models that explore biofilms formed
on vascular catheters, dental devices, and the mucosal surfaces of rats and mice.
Using a mouse model of vaginal candidiasis, Wu et al. demonstrate that C. albicans
strains can form significant quantities of biotic biofilms on the vaginal epithelium.
The formation of these biofilms leads to high resistance to antifungal treatment and
promotes the formation of persister cells, providing new experimental evidence that
extend the role of biofilms in the pathogenesis of vaginal candidiasis. Notably, the
mechanisms employed by C. albicans to colonize and to form biofilms on vulvovaginal
mucosa are thoroughly discussed in the article performed by Rodríguez-Cerdeira et
al., who emphasize the genomic, proteomic and quorum sensing aspects of these biofilms.
In a cohort study, Pentland et al. demonstrate the clinical relevance of biofilms
in voice prosthesis of patients that underwent total laryngectomy, and show that biofilms
are associated with loss of device performance and its early failure. Interestingly,
in most cases of prosthesis failure the investigators found polymicrobial biofilms
composed mainly by Staphylococcus aureus and C. albicans. Indeed, multi-species biofilms
formed by Candida and bacteria can be formed in various niches of the human body,
including the oral cavity, gastrointestinal tract, vulvovaginal region, lungs, and
skin (Lohse et al., 2018). The interactions established by Candida with different
bacterial species have been widely studied (Barbosa et al., 2016; Kong et al., 2016;
Kostoulias et al., 2016), however little is known about the possible interactions
of Candida spp. with other fungi. In pioneering studies, Oliveira et al. and Garcia
et al. demonstrate that C. albicans can form dual species biofilms with Paracoccidioides
brasiliensis or Trichophyton rubrum, respectively. The results of both studies suggest
that C. albicans and P. brasilensis or T. rubrum can coexist in the same environment
and establish fungal-fungal interactions on host surfaces.
The cross-kingdom microbial interactions in biofilms have been explored as a potential
resource for the identification of new antifungal molecules (Scorzoni et al., 2021).
From this perspective, Santos et al. reveal that Streptococcus mutans, an important
bacterium in dental biofilms, can secrete products capable of inhibiting the oral
candidiasis in a murine model. In this work, the authors extracted, fractionated,
and identified the fraction of the S. mutans UA159 culture (SM-F2) with strong activity
against C. albicans and high efficacy in the treatment of oral candidiasis. In an
innovative study, Rossoni et al. explore the antimicrobial activity of bacterial metabolic
products on Candida auris, an emerging multidrug-resistant yeast. The results show
that crude extract derived from the probiotic bacterium Lactobacillus paracasei 28.4
can inhibit the biofilms and persister cells of C. auris, and protect the model host
Galleria mellonella from fungal infection through a direct antifungal activity as
well as by modulating the host immune response. Besides to natural compounds from
microbial origins, plant extracts have gained much attention with large number of
bioactive compounds already isolated and identified (Singla and Dubey, 2019; Scorzoni
et al., 2021). This Research Topic highlights two plant-derived natural compounds:
the coumarin scopoletin (gelseminic acid) studied by Lemos et al. and the palmitic
acid (hexadecenoic acid) studied by Prasath et al. Based on their results, both compounds
exhibit an effective inhibition on biofilms formed by Candida tropicalis. The mechanism
of action of scopoletin involves the alteration on fungal cell and plasma membrane
sterols, while the action of palmitic acid seems associated with ROS-mediated mitochondrial
dysfunction and regulation of ergosterol biosynthesis. Interestingly, scopoletin also
showed activity against the efflux pumps at plasma membrane when combined with fluconazole,
suggesting potential synergistic activity against multidrug-resistant Candida strains.
Looking at therapeutic strategies targeted to Candida biofilms, and based on the evidence
that antiretroviral HIV protease inhibitors can influence the secreted aspartyl proteases
(Saps) of Candida spp. (Cenci et al., 2008; Braga-Silva et al., 2010), Lohse et al.
investigate the capacity of 80 protease inhibitors in preventing and treating Candida
biofilms. Among the 80 protease inhibitors studied, the investigators found that gliotoxin,
acivicin, TPCK and nelfinavir show effectiveness against Candida biofilms. Moreover,
several protease inhibitors exhibit ability to decrease C. albicans biofilms when
combined with caspofungin or amphotericin B. Reddy and Nancharaiah explore new anti-biofilm
approaches using ionic liquids, a novel class of molten salts originates from the
combination of cations and anions, with several applications in chemical industry.
The prospecting results indicate the imidazolium ionic liquid with hexadecyl group
([C16MIM]+[Cl]−) as the most effective compound against C. albicans biofilms. The
antifungal and anti-biofilm activity of imidazolium includes alterations in various
cellular process, such as membrane permeability, ergosterol content, and ROS generation.
Seeking alternative approaches against C. auris, Vazquez-Munoz et al. studied the
use of silver nanoparticles (AgNPs) coated with polyvinylpyrrolidone (PVP) and verified
strong antimicrobial activity on several C. auris strains under planktonic and biofilm
growing conditions. Promisingly, this antimicrobial activity against C. auris strains
is irrespective of their clade, geographical origin, or antifungal-resistant profiles.
Lastly, Vera-González and Shukla discuss the recent advances in antifungal biomaterials
for combating Candida biofilm infections. This review explores the design of nanoparticles
aimed at disrupting existing biofilms and presents innovative technologies that employ
polymer-only coatings as well as coatings with conventional or new antifungal agents
against biofilm formation. Moreover, the authors outline future perspectives in the
development of biomaterials targeted for Candida biofilms, including the use of enzymes
to digest the components of extracellular matrix and identification of new drug targets
such as extracellular vesicles.
We hope that this Research Topic covers the key points of the development, pathogenesis,
and clinical relevance of Candida biofilms, and provides an overview about the progress
and challenges of new antifungal discovery that will incentivize innovation in the
field of Candida biofilm pathogenesis and therapeutics.
Author contributions
JJ and EM wrote the manuscript. All authors contributed to the article and approved
the submitted version.