Prospective Medicines against the Widespread, Emergent, and Multidrugresistant Opportunistic Fungal Pathogen Candida auris: A Breath of Hope.

The emergence of the pathogen Candida auris is a real concern worldwide, especially due to its multidrug resistance profile, besides the difficulties in establishing the correct identification by conventional laboratory methods and its capacity of causing outbreaks in healthcare settings. The limited arsenal of available antifungal drugs, coupled with the lack of momentum for the development of new reagents, represent a challenge in the management of such a pathogen. In this perspective, we have focused on discussing new, promising treatment options for C. auris infections. These novel drugs include an antifungal agent already approved for medical use in the United States of America, compounds that are already in clinical trials and those with potential for repurposing use against this important fungal pathogen.

Surface Characteristics and Microbiological Analysis of a Vat-Photopolymerization Additive-Manufacturing Dental Resin.

The wide application of additive manufacturing in dentistry implies the further investigation into oral micro-organism adhesion and biofilm formation on vat-photopolymerization (VP) dental resins. The surface characteristics and microbiological analysis of a VP dental resin, printed at resolutions of 50 µm (EG-50) and 100 µm (EG-100), were evaluated against an auto-polymerizing acrylic resin (CG). Samples were evaluated using a scanning electron microscope, a scanning white-light interferometer, and analyzed for Candida albicans (CA) and Streptococcus mutans (SM) biofilm, as well as antifungal and antimicrobial activity. EG-50 and EG-100 exhibited more irregular surfaces and statistically higher mean (Ra) and root-mean-square (rms) roughness (EG-50-Ra: 2.96 ± 0.32 µm; rms: 4.05 ± 0.43 µm/EG-100-Ra: 3.76 ± 0.58 µm; rms: 4.79 ± 0.74 µm) compared to the CG (Ra: 0.52 ± 0.36 µm; rms: 0.84 ± 0.54 µm) (p < 0.05). The biomass and extracellular matrix production by CA and SM and the metabolic activity of SM were significantly decreased in EG-50 and EG-100 compared to CG (p < 0.05). CA and SM growth was inhibited by the pure unpolymerized VP resin (48 h). EG-50 and EG-100 recorded a greater irregularity, higher surface roughness, and decreased CA and SM biofilm formation over the CG.

Protease Inhibitors as Promising Weapons against COVID-19: Focus on Repurposing of Drugs used to Treat HIV and HCV Infections.

As a part of the efforts to quickly develop pharmaceutical treatments for COVID-19 through repurposing existing drugs, some researchers around the world have combined the recently released crystal structure of SARS-CoV-2 Mpro in complex with a covalently bonded inhibitor with virtual screening procedures employing molecular docking approaches. In this context, protease inhibitors (PIs) clinically available and currently used to treat infectious diseases, particularly viral ones, are relevant sources of promising drug candidates to inhibit the SARS-CoV-2 Mpro, a key viral enzyme involved in crucial events during its life cycle. In the present perspective, we summarized the published studies showing the promising use of HIV and HCV PIs as potential repurposing drugs against the SARS-CoV-2 Mpro.

Insights into the interaction of Scedosporium apiospermum, Scedosporium aurantiacum, Scedosporium minutisporum, and Lomentospora prolificans with lung epithelial cells.

Scedosporium spp. and Lomentospora prolificans are filamentous fungi that emerged as human pathogens; however, their mechanisms of virulence/pathogenesis are still largely unknown. In the present work, we have evaluated the interaction of S. apiospermum, S. minutisporum, S. aurantiacum, and L. prolificans with lung epithelial cells (A549 line). The results showed that conidia were able to interact with A549 cells, displaying association indexes of 73.20, 117.98, 188.01, and 241.63 regarding S. apiospermum, L. prolificans, S. minutisporum, and S. aurantiacum, respectively. Light microscopy images evidenced morphological changes in epithelial cells, including rounding and detachment, especially during the interaction with L. prolificans. Plasma membrane injuries were detected in A549 cells after 1 h of co-culturing with S. aurantiacum and S. minutisporum and after 4 h with S. apiospermum and L. prolificans, as judged by the passive incorporation of propidium iodide. After 24 h of fungi-epithelial cells interaction, only mycelia were observed covering the A549 monolayer. Interestingly, the mycelial trap induced severe damage in the A549 cells, culminating in epithelial cell death. Our results demonstrate some relevant events that occur during the contact between lung epithelial cells and Scedosporium/Lomentospora species, including conidial adhesion and hyphal growth with consequent irreversible injury on A549 cells, adding light to the infection process caused by these opportunistic and multidrug-resistant fungi.

New and Promising Chemotherapeutics for Emerging Infections Involving Drug-resistant Non-albicans Candida Species.

Fungal infections are a veritable public health problem worldwide. The increasing number of patient populations at risk (e.g. transplanted individuals, cancer patients, and HIV-infected people), as well as the use of antifungal agents for prophylaxis in medicine, have favored the emergence of previously rare or newly identified fungal species. Indeed, novel antifungal resistance patterns have been observed, including environmental sources and the emergence of simultaneous resistance to different antifungal classes, especially in Candida spp., which are known for the multidrug-resistance (MDR) profile. In order to circumvent this alarming scenario, the international researchers' community is engaged in discovering new, potent, and promising compounds to be used in a near future to treat resistant fungal infections in hospital settings on a global scale. In this context, many compounds with antifungal action from both natural and synthetic sources are currently under clinical development, including those that target either ergosterol or ß(1,3)-D-glucan, presenting clear evidence of pharmacologic/pharmacokinetic advantages over currently available drugs against these two well-known fungal target structures. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598, the echinocandin CD101, and the glucan synthase inhibitor SCY-078. In this review, we compiled the most recent antifungal compounds that are currently in clinical trials of development and described the potential outcomes against emerging and rare Candida species, with a focus on C. auris, C. dubliniensis, C. glabrata, C. guilliermondii, C. haemulonii, and C. rugosa. In addition to possibly overcoming the limitations of currently available antifungals, new investigational chemical agents that can enhance the classic antifungal activity, thereby reversing previously resistant phenotypes, were also highlighted. While novel and increasingly MDR non-albicans Candida species continue to emerge worldwide, novel strategies for rapid identification and treatment are needed to combat these life-threatening opportunistic fungal infections.

Fungal Biofilm - A Real Obstacle against an Efficient Therapy: Lessons from Candida.

The past decades have witnessed a dramatic increase in invasive fungal infections, especially caused by different species belonging to the Candida genus. Nowadays, even after many improvements in several medical procedures, Candida infections (candidiasis) still account for an unacceptable high rate of morbimortality in hospital settings. Corroborating this statement, fungal biofilms formed on both abiotic and living surfaces are responsible for an important medical and economic burden, since biofilm lifestyle confers numerous advantages to the pathogens, including high tolerance to environmental stresses such as antimicrobials and host immune responses. Aggravating this scenario, the currently used antifungal drugs have mostly been developed to target exponentially growing fungal cells and are poorly or not effective against biofilm structures. So, the challenges to inhibit biofilm formation (e.g., blocking the fungal adhesion and its fully development due to the changes of physicochemical properties of the inert substrates by covering or impregnating them with antimicrobial compounds, for example, silver nanoparticles) and/or to disarticulate mature biofilm architecture (e.g., by using compounds capable in destabilizing, weakening or destroying the extracellular matrix components, including inhibitors of quorum sensing signals, hydrolytic enzymes, surfactants, chelator agents and biocides) are stimulating researchers around the world to search novel strategies and new chemotherapeutic options to control fungal biofilm. In this context, the present review summarizes some promising approaches and/or strategies that could improve our ability to prevent or eradicate fungal biofilms in medical settings, focusing on the lessons learned with Candida model.