Bruno A. Sousa’s research while affiliated with University of São Paulo and other places

Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse fluconazole resistance of C. albicans clinical isolates. Compounds 1-4, at < 10 μg/ml, ameliorated fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p overexpressing strains to fluconazole. Compounds 1-4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five compounds 1-5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump overexpressing fluconazole resistant C. albicans clinical isolates; isolate 95-142 overexpressing CDR1 and CDR2 , isolate 96-25 overexpressing MDR1 and ERG11 and isolate 12-99 overexpressing CDR1 , CDR2 , MDR1 and ERG11 . Overall, organotellurium compounds 1 and 2 were the most promising fluconazole-chemosensitizers of fluconazole resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps, the ATP-binding cassette (ABC) transporter Cdr1p and the Major Facilitator Superfamily (MFS) transporter Mdr1p.

Leishmania (Leishmania) infantum chagasi is one of the agents that cause visceral leishmaniasis. This disease occurs more frequently in third world countries, such as Brazil. The treatment is arduous, and is dependent on just a few drugs like the antimonial derivatives and amphotericin B. Moreover, these drugs are not only expensive, but they can also cause severe side effects and require long-term treatment. Therefore, it is very important to find new compounds that are effective against leishmaniasis. In the present work we evaluated a new group of synthetic amides against the promastigote and amastigote forms of L. infantum chagasi. The results showed that one of these amides in particular, presented very effective activity against the promastigotes and amastigotes of L. infantum chagasi at low concentrations and it also presented low toxicity for mammal cells, which makes this synthetic amide a promising drug for combating leishmaniasis.

The confinement of a biocatalyst designed to operate under continuous-flow conditions is a strategy developed by nature in order to achieve efficient reactions in biological media. Herein, we present a mimetic model that employs a confined lipase (CAL-B) in the production of several carboxamide derivatives from esters as precursors. The remarkable selectivity of such system is also described when α,β-unsatured carboxylic substrates are employed.

The confinement of a biocatalyst designed to operate under continuous-flow conditions is a strategy developed by nature in order to achieve efficient reactions in biological media. Herein, we present a mimetic model that employs a confined lipase (CAL-B) in the production of several carboxamide derivatives from esters as precursors. The remarkable selectivity of such system is also described when α,β-unsatured carboxylic substrates are employed.

In recent decades the need for new chiral compounds with high enantiomeric excesses has been rapidly emerging. Among the various methods used to achieve chiral compounds, one can highlight the enzymatic kinetic resolution of racemic esters, alcohols and amines and as the most versatile enzymatic methodology used in organic routes. Enzymes are used in biocatalytic routes to obtain enriched and enantiomerically pure compounds. The most remarkable biocatalysts for these processes are lipases, which have the capability of being used in organic media. Thus, the main purpose of this article was to present a review about studies conducted in Brazil involving the kinetic resolution of racemic compounds using lipases, also including unusual substrates containing heteroatoms, such as boron, silicon, selenium, tellurium and sulfur.

Enzymatic kinetic resolution (EKR) of (±)-cyanohydrins was performed by using immobilized lipase from Candida antarctica (CALB) under conventional ordinary conditions (orbital shaking) and under microwave radiation (MW). The use of microwave radiation contributed very expressively on the reduction of the reaction time from 24 to 2 h. Most importantly, high selectivity (up to 92% eep) as well as conversion was achieved under MW radiation (50-56%).

This account covers the synthesis and biological applications of organoseleno- and organotelluro-based molecular dyes. The most relevant applications for photodynamic therapy (PDT), fluorescent probes for the detection of endogenous reactive oxygen species (ROS), natural bioreductors like glutathione (GSH) and metals present in physiological systems will be discussed. This manuscript covers only dyes bearing small selenium- and tellurium-containing heterocycles.

Background Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. The Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. The present study investigated the effects of 13 synthetic compounds on Pdr5p.ResultsAmong the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 ¿M and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 ¿M. When tested at 100 ¿M, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans.Conclusions We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.