Anti-Acanthamoeba metallopharmaceuticals: Amoebicidal activity and synergistic effect of copper(II) coordination compound.

Acanthamoeba spp. emerged as a clinically important pathogen related to amoebic keratitis. It is among the main causes of corneal transplantation and vision loss in ophthalmology. The treatment protocols have a low cure rate, high toxicity, and need for drug combination. Transition metal compounds have shown promising antiprotozoal effects. This study evaluates the amoebicidal activity of copper(II) coordination compounds in combination with chlorhexidine and the cytotoxicity to topical ocular application. These copper(II) coordination compounds were screened against Acanthamoeba castellanii trophozoites (ATCC 50492). The cytotoxicity on rabbit corneal cell line (ATCC-CCL 60) was performed. The compounds showed high amoebicidal potential, with inhibition of trophozoite viability above 80%. The Cp12 and Cp13 compounds showed Minimal Inhibitory Amoebicidal Concentration (MIAC) at 200 µM and mean inhibitory concentration (IC50) values lower than 10 µM. Against the cysts, Cp12 showed a reduction in viability (48%) in the longest incubation period. A synergistic effect for Cp12 with chlorhexidine was observed. The compounds have a dose-dependent effect against rabbit corneal cells. Compound Cp12 has potential for future application in developing ophthalmic formulations against Acanthamoeba keratitis and its use in multipurpose solutions is highlighted.

Antifungal activity of azoles, allylamines, and 8-hidroxiquinolines, alone and in combination, against Malassezia pachydermatis in vitro and in vivo.

Malassezia pachydermatis is often reported as the causative agent of dermatitis in dogs. This study aims to evaluate the in vitro and in vivo antifungal activity of azoles and terbinafine (TRB), alone and in combination with the 8-hydroxyquinoline derivatives (8-HQs) clioquinol (CQL), 8-hydroxyquinoline-5-(n-4-chlorophenyl)sulfonamide (PH151), and 8-hydroxyquinoline-5-(n-4-methoxyphenyl)sulfonamide (PH153), against 16 M. pachydermatis isolates. Susceptibility to the drugs was evaluated by in vitro broth microdilution and time-kill assays. The Toll-deficient Drosophila melanogaster fly model was used to assess the efficacy of drugs in vivo. In vitro tests showed that ketoconazole (KTZ) was the most active drug, followed by TRB and CQL. The combinations itraconazole (ITZ)+CQL and ITZ+PH151 resulted in the highest percentages of synergism and none of the combinations resulted in antagonism. TRB showed the highest survival rates after seven days of treatment of the flies, followed by CQL and ITZ, whereas the evaluation of fungal burden of dead flies showed a greater fungicidal effect of azoles when compared to the other drugs. Here we showed for the first time that CQL is effective against M. pachydermatis and potentially interesting for the treatment of malasseziosis.

Development of a Clioquinol Nanocarrier as a New, Promising Option for the Treatment of Dermatomycosis.

Dermatomycosis is a common fungal infection, and its treatment is limited by few antifungal agents. Clioquinol (CQ) is an antiparasitic agent that has been studied for new uses, such as antifungal and antiviral applications. CQ was incorporated into a lipid-based nanocarrier as a new, promising option for dermatomycosis. This study aimed to develop a CQ-loaded lipid-based nanocarrier for cutaneous application and to evaluate its antifungal activity. CQ-loaded nanoformulation (LBN-CQ) was developed using the ultrasonication method, and the particle size, polydispersity index (PDI), pH, zeta potential, and drug content were monitored for 45 days. To evaluate antifungal activity, broth microdilution and a time-kill assay were performed. LBN-CQ presented a particle size of 91 ± 3 nm and PDI of 0.102 ± 0.009. The zeta potential and pH values were -9.7 ± 2.0 mV and 6.0 ± 0.1, respectively. The drug content was 96.4 ± 2.3%, and the encapsulation efficiency was 98.4%. LBN-CQ was able to reduce the minimum inhibitory concentration (MIC) in a 2-fold or 4-fold manner in most of the tested strains. Additionally, LBN-CQ presented stable fungistatic action that was not concentration- or time-dependent. In conclusion, the developed CQ-loaded nanocarrier is a promising treatment for skin fungal infections and a promising candidate for future randomized clinical trials.

Marxismo e psicologia comunitária: uma relação presente na psicologia brasileira? / Marxism and community psychology: a relationship present in Brazilian psychology?

Este trabalho apresenta uma pesquisa que explorou a hipótese de que o Marxismo foi fundamento importante na história da Psicologia Comunitária no Brasil. Após apresentar o percurso histórico da Psicologia Comunitária no Brasil e expor descrições sobre o Marxismo, o trabalho apresenta os resultados de um estudo bibliográfico. Foram analisados 12 trabalhos publicados na década de 1980. A análise destacou: a relação com a teoria marxista; função social e deselitização da Psicologia; concepção histórico-social de indivíduo; e presença da noção freireana de conscientização. A partir da análise o trabalho apresenta considerações críticas sobre a relação entre teoria marxista e Psicologia Comunitária destacando: a presença residual do Marxismo como fundamento teórico, a importância de categorias marxistas para problematizar a relação entre Psicologia e sociedade e os limites dos projetos de transformação social na Psicologia Comunitária.

A chloroacetamide derivative as a potent candidate for fusariosis treatment.

Fusariosis has presented a significant increase in their incidence in the last years. This epidemiological panorama probably is due to the increasing profile of refractory susceptibility of Fusarium spp. to available drugs, especially in immunocompromised individuals. Thus, the development of new compounds with effectiveness on these organisms is a necessity. This study evaluated the antifungal potential of a chloroacetamide derivative (4-BFCA) against resistant Fusarium strains. As a result, the compound was effective against all strains (MIC range 12.5-50 µg/mL). The time kill assay demonstrated that 4-BFCA presents a concentration-dependent fungicidal action. Although its action mechanism has not yet been elucidated, it was possible to observe its efficacy through damages and alterations provoked along the hyphae of Fusarium spp. 4-BFCA maintained a high survival rate of Tenebrio molitor larvae, suggesting that it does not cause acute systemic toxicity on this host at the concentration evaluated. In addition, 4-BFCA was 83.33% effective in combating a fungal infection in vivo on the chorioallantoid membrane of embryonated eggs. Our results are very promising and arouse interest to investigate the action of 4-BFCA on Fusarium strains since it acts as a possible candidate for the development of new therapies for the treatment of fusariosis.

Thiocyanate toxicity: a teaching case.

Introduction: Thiocyanate can cause gastrointestinal, neurologic, and cardiovascular toxicity. Additionally, it interferes with multiple laboratory assays. We present a case of acute thiocyanate toxicity. Case: A 17-year-old female presented with an intentional thiocyanate ingestion. Her course was notable for delirium, wide complex tachycardia, and presumed seizure activity with concurrent lactatemia, acidemia, and narrowing of her arterio-venous oxygen gradient. She received lipid emulsion therapy (LET). While hemodialysis was considered, she recovered without additional treatment. After resolution of her critical illness, a serum cyanide concentration was 0.21 mcg/mL. She had laboratory testing notable for hyperchloremia, hypocalcemia, hypokalemia, and an elevated salicylate concentration attributed to interference by thiocyanate. The thiocyanate was eliminated via first-order kinetics with a half-life of 61.6 hours. Discussion: Thiocyanate poisoning may cause cardiac and neurologic toxicity. Laboratory evidence of impaired cellular respiration in this case suggests possible in vivo conversion to cyanide, however this is not proven. Cyanide antidotal treatment was not administered for this patient, however LET was given based on thiocyanate's lipophilicity. Hemodialysis is known to effectively remove thiocyanate from the blood, however the patient improved without it. The patient's laboratory derangements were due to thiocyanate interference with ion selective electrode and colorimetric analyzer technology. Conclusions: Thiocyanate can cause cardiac and neurologic toxicity, and interferes with several laboratory assays. Theoretically, LET and cyanide antidotal treatment may be useful, but this requires further investigation. Thiocyanate toxicity should be managed supportively, and hemodialysis may be used in severe cases.

Measurement of Severe Acute Respiratory Syndrome Coronavirus 2 Antigens in Plasma of Pediatric Patients With Acute Coronavirus Disease 2019 or Multisystem Inflammatory Syndrome in Children Using an Ultrasensitive and Quantitative Immunoassay.

BACKGROUND: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). METHODS: Plasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n = 36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n = 53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n = 67) or within 24 hours of negative RT-PCR (n = 43). RESULTS: Specificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28-3844 pg/mL (N) and 1.65-1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. CONCLUSIONS: Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.

Corticosteroid therapy associated with COVID-19: an ally or a risk factor for the establishment of secondary fungal co-infections?

Corticosteroid therapy to combat inflammation caused by SARS-CoV-2 seems to be a risk factor for developing secondary fungal co-infections. PubMed and ScienceDirect databases were searched, with the following word groups: [(aspergillosis OR mucormycosis OR candidiasis) AND (coronavirus disease) AND (corticoids). The selected articles present the main risk factors related to the establishment of secondary fungal co-infections in COVID-19 patients. Corticosteroid therapy used to combat inflammation caused by SARS-CoV-2 has been shown to be strongly associated with the establishment of mucormycosis and aspergillosis. Mucormycosis has been the main fungal co-infection related to corticosteroid therapy, causing a high number of deaths in COVID-19 patients. Diabetes mellitus was the most prevalent comorbidity, especially for the establishment of mucormycosis. Dexamethasone use seems to be associated with mucormycosis emergence and death. However, aspergillosis showed a greater relationship with patient recovery. Thus, risk factors such as diabetes mellitus, combined with corticosteroid use, have shown a relationship to the establishment of mucormycosis. The corticosteroids used in COVID-19 patients should be individually analyzed, considering the patient's medical history and the risk/benefit ratio of the use of these drugs.

Measurement of SARS-CoV-2 antigens in plasma of pediatric patients with acute COVID-19 or MIS-C using an ultrasensitive and quantitative immunoassay.

BACKGROUND: Detection of SARS-CoV-2 antigens in blood has high sensitivity in adults with acute COVID-19, but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). METHODS: Plasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n=36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n=53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n=67) or within 24h of negative RT-PCR (n=43). RESULTS: Specificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity, respectively; sensitivity in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤ 35 were 93%/63%. Antigen concentrations ranged from 1.28-3,844 pg/mL (N) and 1.65-1,071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. CONCLUSIONS: Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis. KEY POINTS: In a U.S. pediatric cohort tested with ultrasensitive immunoassays, SARS-CoV-2 nucleocapsid antigens were detectable in most patients with acute COVID-19, and spike antigens were commonly detectable. Both antigens were undetectable in almost all MIS-C patients.

Antifungal Efficacy and Safety of Cycloheximide as a Supplement in Optisol-GS.

PURPOSE: The incidence of fungal infection after corneal transplant has increased significantly in recent years, especially Candida spp. This study aimed to evaluate the efficacy and safety of the addition of cycloheximide in Optisol-GS media in decreasing the growth of Candida spp. strains. METHODS: This in vitro laboratory efficacy study measured fungal colony growth in 24 vials of Optisol-GS that were divided into 6 groups of 4 vials each, as follows: (1) MIC/2 cycloheximide, (2) MIC cycloheximide, (3) MICx5 cycloheximide, (4) MICx10 cycloheximide, from MIC values obtained for each strain, (5) unsupplemented optisol-GS as a positive control (added inoculum), and (6) unsupplemented optisol-GS as a negative control (no inoculum). In each group was added Candida albicans, C. glabrata and C. parapsilosis, except in the negative control. The evaluated variables were fungal colony growth from the Optisol-GS vials, corneal endothelial cell density and endothelial cell viability at different concentrations of cycloheximide. RESULTS: In the efficacy study, all strains showed a reduction in fungal cell growth from the second day at all evaluated concentrations of optisol-GS supplemented with cycloheximide, even at subinhibitory concentrations (MIC/2). For C. glabrata, the colony count was reduced to 99%. No evidence of corneal endothelial toxicity was found at any concentration, in the safety study, compared with the paired control. CONCLUSION: The addition of cycloheximide to optisol-GS decreased the fungal growth, demonstrating fungicide action against C. glabrata and fungistatic action against C. albicans and C. parapsilosis. This drug did not demonstrate toxicity to the corneal endothelium at different concentrations.

Bacteriophages as surrogates for the study of viral dispersion in open air.

The SARS-CoV-2 pandemic has revived the debate about the routes of virus transmission and their likelihoods. It is of utmost importance to assess the risks of contamination of susceptible people by infectious individuals and to evaluate the level of SARS-CoV-2 and other respiratory viruses transmission in the community. Most countries have imposed non-pharmaceutical measures to contain SARS-CoV-2 transmission, including physical distancing and mask wearing. Here we evaluated the spreading of viruses in open air using harmless Escherichia coli bacteriophages as a surrogate. Phages were sprayed towards Petri dishes seeded with bacteria at different lengths and angles. Our results showed that the transmission rate decreased exponentially with distance. The highest recorded transmission rate was [Formula: see text] PFU/plate when phages were sprayed from a 1 m distance, suggesting that the probability of transmission of a single virus at a 1 m distance is 1:100,000.

Ex vivo potential of a quinoline-derivative nail lacquer as a new alternative for dermatophytic onychomycosis treatment.

Introduction. Onychomycosis infections currently show a significant increase, affecting about 10 % of the world population. Trichophyton rubrum is the main agent responsible for about 80 % of the reported infections. The clinical cure for onychomycosis is extremely difficult and effective new antifungal therapy is needed.Hypothesis/Gap Statement. Ex vivo onychomycosis models using porcine hooves can be an excellent alternative for evaluating the efficacy of new anti-dermatophytic agents in a nail lacquer.Aim. Evaluation of the effectiveness of a nail lacquer containing a quinoline derivative on an ex vivo onychomycosis model using porcine hooves, as well as the proposal of a plausible antifungal mechanism of this derivative against dermatophytic strains.Methodology. The action mechanism of a quinoline derivative was evaluated through the sorbitol protection assay, exogenous ergosterol binding, and the determination of the dose-response curves by time-kill assay. Scanning electron microscopy evaluated the effect of the derivative in the fungal cells. The efficacy of a quinoline-derivative nail lacquer on an ex vivo onychomycosis model using porcine hooves was evaluated as well.Results. The quinoline derivative showed a time-dependent fungicidal effect, demonstrating reduction and damage in the morphology of dermatophytic hyphae. In addition, the ex vivo onychomycosis model was effective in the establishment of infection by T. rubrum.Conclusion. Treatment with the quinoline-derivative lacquer showed a significant inhibitory effect on T. rubrum strain in this infection model. Finally, the compound presents high potential for application in a formulation such as nail lacquer as a possible treatment for dermatophytic onychomycosis.

Competition for nutritional resources masks the true frequency of bacterial mutants.

BACKGROUND: It is widely assumed that all mutant microorganisms present in a culture are able to grow and form colonies, provided that they express the features required for selection. Unlike wild-type Escherichia coli, PHO-constitutive mutants overexpress alkaline phosphatase and hence can hydrolyze glycerol-2-phosphate (G2P) to glycerol and form colonies on plates having G2P as the sole carbon source. These mutations mostly occur in the pst operon. However, the frequency of PHO-constitutive colonies on the G2P selective plate is exceptionally low. RESULTS: We show that the rate in which spontaneous PHO-constitutive mutations emerge is about 8.0 × 10-6/generation, a relatively high rate, but the growth of most existing mutants is inhibited by their neighboring wild-type cells. This inhibition is elicited only by non-mutant viable bacteria that can take up and metabolize glycerol formed by the mutants. Evidence indicates that the few mutants that do form colonies derive from microclusters of mutants on the selective plate. A mathematical model that describes the fate of the wild-type and mutant populations under these circumstances supports these results. CONCLUSION: This scenario in which neither the wild-type nor the majority of the mutants are able to grow resembles an unavoidable "tragedy of the commons" case which results in the collapse of the majority of the population. Cooperation between rare adjacent mutants enables them to overcome the competition and eventually form mutant colonies. The inhibition of PHO-constitutive mutants provides an example of mutant frequency masked by orders of magnitude due to a competition between mutants and their ancestral wild-type cells. Similar "tragedy of the commons-like" cases may occur in other settings and should be taken into consideration while estimating true mutant frequencies and mutation rates.

Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis.

Fungal infections have emerged as a current serious global public health problem. The main problem involving these infections is the expansion of multidrug resistance. Therefore, the prospection of new compounds with efficacy antifungal becomes necessary. Thus, this study evaluated the antifungal profile and toxicological parameters of quinolines derivatives against Candida spp. and dermatophyte strains. As a result, a selective anti-dermatophytic action was demonstrated by compound 5 (geometric means (GM = 19.14 µg ml-1)). However, compounds 2 (GM = 50 µg ml-1) and 3 (GM = 47.19 µg ml-1) have presented only anti-Candida action. Compounds 3 and 5 did not present cytotoxic action. Compound 5 did not produce dermal and mucosal toxicity. In addition, this compound showed the absence of genotoxic potential, suggesting safety for topical and systemic use. Quinolines demonstrated a potent anti-dermatophytic and anti-yeast action. Moreover, compound 5 presented an excellent toxicological profile, acting as a strong candidate for the development of a new effective and safe compound against dermatophytosis of difficult treatment.

Influence of detergents and sodium hypochlorite on Yarrowia lipolytica biofilms in utensils used in industrial production of colonial cheese.

The formation of microbial biofilms in materials used in the industrial production of dairy may lead to deterioration of these foods. Yarrowia lipolytica biofilms are widely found in dairy products and can modify the final characteristics of these products. Thus, this study investigated the effectiveness of hygienization by detergents and sodium hypochlorite on the formation of Y. lipolytica biofilms in different utensils usually employed during industrial cheese production, like polypropylene, hoses, and nylon/polyethylene. The utensils were sanitized using solutions of mild and alkaline detergents, and sodium hypochlorite, according to the cheese industry Standard Operation Procedure. Results showed that in all coupons there was biofilm formation with Y. lipolytica isolates. The contact angle measurements were favored to promote the adhesion of the biofilm in the evaluated surfaces. Even after treatment with sanitizers, a significant survival rate of planktonic cells was observed in all coupons tested. These results indicate that Y. lipolytica biofilms show a significant ability to adhere to polypropylene, presenting an important impact on the quality of colonial cheese.

Design, synthesis, and evaluation of novel 2-substituted 1,4-benzenediol library as antimicrobial agents against clinically relevant pathogens.

Development of new antimicrobial agents, capable of combating resistant and multidrug-resistant fungal and bacterial clinical strains, is necessary. This study presents the synthesis and antimicrobial screening of 42 2-substituted-1,4-benzenediols, being 10 novel compounds. In total, 23 compounds showed activity against fungi and/or bacteria. Benzenediol compounds 2, 5, 6, 8, 11, and 12 demonstrated broad spectrum antimicrobial actions, including resistant and multidrug-resistant species of dermatophytes (Trichophyton mentagrophytes), Candida spp. and the ESKAPE panel of bacteria. Minimum inhibitory concentrations of these compounds for fungi and bacterial strains ranged from 25 to 50 µg/ml and 8-128 µg/ml, respectively. The antifungal mechanism of action is related to the fungal cell wall of dermatophytes and membrane disruption to dermatophytes and yeasts, in the presence of compound 8. Specific structural changes, such as widespread thinning along the hyphae and yeast lysis, were observed by scanning electron microscopy. The effects of compound 8 on cell viability are dose-dependent; however they did not cause genotoxicity and mutagenicity in human leukocyte cells nor haemolysis. Moreover, the compounds were identified as nonirritant by the ex-vivo Hen's egg test-chorioallantoic membrane (HET-CAM). The furan-1,4-benzenediol compound 5 showed in vivo efficacy to combat S. aureus infection using embryonated chicken eggs. Therefore, the compounds 8, and 5 are promising as hits for the development of new antimicrobial drugs with reduced toxicity.

Sitosterolemia-10 years observation in two sisters.

Familial hypercholesterolemia due to heterozygous low-density lipoprotein-receptor mutations is a common inborn errors of metabolism. Secondary hypercholesterolemia due to a defect in phytosterol metabolism is far less common and may escape diagnosis during the work-up of patients with dyslipidemias. Here we report on two sisters with the rare, autosomal recessive condition, sitosterolemia. This disease is caused by mutations in a defective adenosine triphosphate-binding cassette sterol excretion transporter, leading to highly elevated plant sterol concentrations in tissues and to a wide range of symptoms. After a delayed diagnosis, treatment with a diet low in plant lipids plus ezetimibe to block the absorption of sterols corrected most of the clinical and biochemical signs of the disease. We followed the two patients for over 10 years and report their initial presentation and long-term response to treatment.

Chloroacetamide derivatives as a promising topical treatment for fungal skin infections.

The aim of this study was to evaluate the antifungal potential of 11 chloroacetamide derivatives and derivative incorporated into a film-forming system (FFS) as a potential alternative for the topical treatment of superficial and skin mycoses. The minimum inhibitory concentration (MIC) evaluation followed Clinical and Laboratory Standards Institute protocols M27-A3 (Candida) and M28-A2 (dermatophytes). Compounds 2, 3, and 4 were the most effective against Candida species (MIC range: 25-50 µg/mL) and dermatophytes (MIC range: 3.12-50 µg/mL). Compound 2 maintained its antifungal activity when incorporated in a FFS, with MIC values equivalent to the free compound. In addition, the compound does not act through complexation with ergosterol, suggesting that it may act on other targets of the fungal cell membrane. Chloroacetamide derivatives presented anti-Candida and anti-dermatophytic effectiveness. The FFS containing compound 2 has shown to be superior to traditional topical treatment of superficial and cutaneous fungal infections. It was found that these new chemical entities, with their applicability, are an excellent alternative to the topical treatment of fungal skin infections.

Lipid core nanoparticles as a broad strategy to reverse fluconazole resistance in multiple Candida species.

Fungal resistance is the major problem related to fluconazole treatments. This study aims to develop innovative lipid core nanocapsules and nanostructured lipid carriers containing fluconazole, to study in vitro antifungal activity and to assess the possibility of resistance reversion in Candida albicans, C. glabrata, C. krusei, and C. tropicalis isolates. The action mechanism of nanoparticles was investigated through efflux pumps and scanning electron microscopy studies. The lipid core nanocapsules and nanostructured lipid carriers were prepared by interfacial deposition of preformed polymer and high-pressure homogenization methods, respectively. Both nanostructures presented sizes below 250 nm, SPAN < 1.6, negative zeta potential, pH slightly acid, high drug content and controlled drug release. The nanostructured lipid carriers were unable to reverse the fungal resistance. Lipid core nanoparticles displayed advantages such as a reduction in the effective dose of fluconazole and resistance reversion in all isolates tested - with multiple mechanisms of resistance. The main role of the supramolecular structure and the composition of the nanoparticles on antifungal mechanisms of action were discussed. The results achieved through this study have an impact on clinical therapy, with a potential application in the treatment of fungal infections caused by resistant isolates of Candida spp.

Clioquinol is a promising preventive morphological switching compound in the treatment of Candida infections linked to the use of intrauterine devices.

PURPOSE: Candida biofilm infections are frequently linked to the use of biomaterials and are of clinical significance because they are commonly resistant to antifungals. Clioquinol is an antiseptic drug and is effective against multidrug-resistant Candida. We investigated the effect of clioquinol and two other 8-hydroxyquinoline derivatives on Candida biofilm. METHODOLOGY: The ability to inhibit biofilm formation, inhibit preformed biofilm and remove established biofilms was evaluated using in vitro assays on microtitre plates. The action of clioquinol on biofilm in intrauterine devices (IUDs) was also investigated, describing the first protocol to quantify the inhibitory action of compounds on biofilms formed on IUDs. RESULTS: Clioquinol was found to be the most effective 8-hydroxyquinoline derivative among those tested. It prevented more than 90 % of biofilm formation, which can be attributed to blockade of hyphal development. Clioquinol also reduced the metabolic activity of sessile Candida but the susceptibility was lower compared to planktonic cells (0.031-0.5 µg ml-1 required to inhibit 50 % planktonic cells and 4-16 µg ml-1 to inhibit 50 % preformed biofilms). On the other hand, almost complete removal of biofilms was not achieved for the majority of the isolates. Candida spp. also showed the ability to form biofilm on copper IUD; clioquinol eradicated 80-100 % of these biofilms. CONCLUSION: Our results indicate a potential application in terms of biomaterials for 8-hydroxyquinoline derivatives. Clioquinol could be used as a coating to prevent morphological switching and thus prevent biofilm formation. Furthermore, clioquinol may have future applications in the treatment of Candida infections linked to the use of IUDs.