Recent developments on the anti-Candida effect of amphotericin B combined with a second drug - a mini-review.

Invasive Candida infections threaten human health due to the increasing incidence of resistance to the currently available antifungal agents. Amphotericin B (AMB) is the gold standard therapy to treat these infections. Nevertheless, the use of such substance in the clinic is aggravated by its toxicity. Since AMB binds to membrane sterols, it forms pores on human plasma membranes, mainly in kidney cells, leading to nephrotoxicity. The combination of this drug to a second substance could allow for the use of smaller concentrations of AMB, consequently lowering the probability of adverse effects. This mini-review summarizes information regarding an array of substances that enhance AMB antifungal activity. It may be noticed that several of these compounds target plasma membrane. Interestingly, substances approved for human use also presented combinatory anti-Candida activity with AMB. These data reinforce the potential of associating AMB to another drug as a promising therapeutical alternative to treat Candida infections. Further studies, regarding mechanism of action, pharmacokinetics and toxicity parameters must be conducted to confirm the role of these substances as adjuvant agents in candidiasis therapy.

Anti-Leishmania amazonensis activity of the marine sponge Dercitus (Stoeba) latex (Porifera) from São Pedro and São Paulo Archipelago, Pernambuco, Brazil.

The search for new therapeutic strategies for leishmaniasis treatment is essential due to the side effects of available drugs and the increasing incidence of resistance to them. Marine sponges use chemical compounds as a defense mechanism, and several of them present interesting pharmacological properties. The aim of this study was to evaluate the in vitro activity of the aqueous extract of the marine sponge Dercitus (Stoeba) latex against Leishmania amazonensis. MIC and toxicity against mammal cells were evaluated through broth microdilution assays. Transmission electron microscopy analysis was performed to assess possible effects on L. amazonensis ultrastructure. Arginase and proteolytic activities were measured by spectrometric methodologies. The extract of Dercitus (Stoeba) latex displayed antileishmanial activity and moderate toxicity against peritonial macrophages. Ultrastructural changes were observed after the growth of L. amazonensis promastigotes in the presence of the extract at 150 µg.ml-1 (IC50), mainly on acidocalcysomes. The extract was able to inhibit the activity of arginase and serine proteases. This study shows that Dercitus (Stoeba) latex aqueous extract may be a novel potential source of protozoa protease inhibitors and drugs that are less toxic to be used in the treatment of L. amazonensis infections.

Candida albicans Clinical Isolates from a Southwest Brazilian Tertiary Hospital Exhibit MFS-mediated Azole Resistance Profile.

Candida albicans is the most frequent fungal species that causes infections in humans. Fluconazole is the main antifungal used to treat Candida infections, and its prolonged and indiscriminate use for the last decades are the most established causes which originated resistant strains. Fungal drug resistance is associated to alterations in ERG11 gene and overexpression of multidrug resistance (MDR) transporters belonging to two families: ATP-binding cassette (ABC) and Major Facilitator Superfamily (MFS). To evaluate the role of MFS transporters in azoles resistance of C. albicans clinical strains, this study aimed to analyze four Candida albicans clinical isolates from the University Hospital in Juiz de Fora (Minas Gerais/Brazil), selected in our previous study as they were unaffected by FK506, an ABC pumps inhibitor. In a primary investigation on MFS proteins overexpression, the extrusion of fluorescent substrates (rhodamine 6G and nile red) was analyzed by fluorescence microscopy and flow cytometry. Results suggest participation of MFS transporters in azole resistance of C. albicans isolates and indicate the existence of secondary resistance mechanisms. Therefore, this study contributes to the information about Candida albicans infections in Brazil and reinforces the importance of epidemiological studies focusing on an improved understanding of the disease and further resistance reversion.

Histatin 5 and human lactoferrin inhibit biofilm formation of a fluconazole resistant Candida albicans clinical isolate.

Candida albicans is the most important fungal pathogen that causes infections in humans. Biofilms are hard-to-treat structures due to their high antifungal resistance. Saliva is a fluid that contains antimicrobial substances acting as the first-line of defense against pathogens, and its immune components may be potential tools for the discovery of new treatments against candidiasis. To evaluate the activity of histatin 5 and human lactoferrin against biofilm formation. A fluconazole-resistant Candida albicans clinical isolate was used as the model microorganism. Morphogenesis was evaluated by differential counting. Biofilm quantification was performed by XTT reduction assay. Thickness and topography of biofilms were assessed through confocal laser scanning microscopy (CLSM). Histatin 5 inhibited yeast-to-hyphae transition in a dose-dependent manner, while the effect of human lactoferrin on this process was inversely proportional to its concentration. Both compounds were able to significantly inhibit biofilm metabolic activity. Histatin 5 reduced biofilm thickness. Histatin 5 and human lactoferrin exhibited in vitro cytotoxicity against a fluconazole-resistant Candida albicans biofilm, which points to the potential application of these compounds in the treatment of biofilms formed by this fungus, especially in resistant infections.