Paracoccidioides brasiliensis, Paracoccidioidomycosis, and Antifungal Antibiotics

Abstract

Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), a human systemic, chronic and progressive mycosis. Preferred antifungals are sulfamethoxazol-trimethoprim, itraconazole, amphotericin B. Treatment is lengthy, the drugs may have undesirable side effects, and some are costly. Occasional resistant strains have been reported. Therefore, the search for more selective and efficient antifungals to treat this and other mycoses continues. Ajoene, chemically derived from garlic, behaves as an antifungal agent against P. brasiliensis and other fungi. Its antiproliferative effects in P. brasiliensis are associated with a reduction of phosphatidyl choline, a concomitant increase in its precursor phosphatidyl ethanolamine, and a large increase in unsaturated fatty acids in the pathogenic yeast phase. The sterol biosynthetic pathway has been largely studied for the search of antifungals. Azoles and allilamines act on differents steps of this pathway. However, they may interfere with similar steps in the host. Hence, the search for drugs that may act on more specific steps is ongoing. One such step focuses on the sterol C-methylations catalyzed by the enzyme (S)-adenosyl-L-methionine: Delta(24) - sterol methyl transferase (SMT). SMT inhibitors such as azasterols and derivatives (AZA1, AZA2, AZA3) have proven highly effective as antiproliferative agents against protozoa and some fungi, among them, P. brasiliensis. Their chemical synthesis and structure, and their molecular electrostatic potential are discussed in order to understand their mechanism of action, and derive rationally designed improvements on these molecules, that would favour a higher efficacy and selectivity.

Paracoccidioides brasiliensis: chemical and molecular tools for research on cell walls, antifungals, diagnosis, taxonomy

“…Both mechanisms are common to the fungal pathogen and the host and consequently, drugs that interfere with them affect selectivity towards the pathogen, hence their undesirable side effects. However, differences exist in primary metabolism between mammals and other eukaryotes such as plants, fungi and protozoa [59]. While mammals synthesize C 27 cholestane-based members of the steroid family, pathogenic fungi, protozoa and plants require the presence of endogenous sterols C 28 -C 29 (typically ergosterol and 24-alkyl analogs) which act as essential growth factors for these organisms.…”

“…While mammals synthesize C 27 cholestane-based members of the steroid family, pathogenic fungi, protozoa and plants require the presence of endogenous sterols C 28 -C 29 (typically ergosterol and 24-alkyl analogs) which act as essential growth factors for these organisms. The enzyme responsible for the addition of these alkyl groups to carbon C-24 and for the regulation of carbon flow in the sterol pathway is the D (24) -sterol methyl transferase (SMT) [59,60]. With this in mind, new compounds were synthesized.…”

“…With regards to the sterol hydrazones, H1, H2 and H3 inhibited SMT, in a manner dependent on the stereochemical location of the hydrazone group. H4, instead, induced a good antiproliferative activity not associated with blockage of any step in the pathway to sterol biosynthesis, suggesting a different mode of action [Visbal et (4) lanosterol [59]. Reproduced by permission In order to develop rational criteria for the development of antifungals, molecular modeling is used to study the molecular conformation in solution of drug candidates, by means of the molecular electrostatic potential (MEP), obtained from Quantum Mechanical ab initio calculations.…”

“…This conformation probably orientates AZA1 N lone pair in such a way that it inhibits SMT by strongly interacting with the enzyme from the right side of its active site. The different conformations in the piperidine rings of AZA2 and AZA3 are due to the absolute configuration of the hydroxyl group (S) in C-22 [59]. In AZA2, the N atom is in the sterol plane, and its lone pair is oriented toward the sterol nucleus, configuration that greatly decreases AZA2-SMT interaction by effect of the steric hindrance produced by the piperidine ring.…”

“…This allows a stronger interaction with the positive charge in the active site of SMT. When a comparison is made between the b-orientation of the lanosterol side chain and the equivalent one of AZA3, one finds that the N lone pair has a similar orientation in the space as the p-orbitals of the D 24 -bond of lanosterol [59].…”