Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

Bagatin, Mariane Cristovão; Pimentel, Arethusa Lobo; Biavatti, Débora Carina; Basso, Ernani A.; Kioshima, Érika Seki; Seixas, Flávio Augusto Vicente; Gauze, Gisele F.

doi:10.1128/aac.00165-17

Cited by 17 publications

(21 citation statements)

References 54 publications

(44 reference statements)

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“…Rational drug design involves the use of computational tools in drug discovery as a cost-effective alternative to traditional experimental protocols [41]. Several research groups have shown the excellent antifungal potential of compounds selected by virtual screening of small molecule libraries against specific targets [26,39,[42][43][44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Promising antifungal activity of new oxadiazole against Candida krusei

et al. 2020

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Candida krusei is one of the most common agents of invasive candidiasis and candidemia worldwide, leading to high morbidity and mortality rates. This species has become a problem due to its intrinsic resistance and reduced susceptibility to azoles and polyenes. Moreover, the number of antifungal drugs available for candidiasis treatment is limited, demonstrating the urgent need for the discovery of novel alternative therapies. In this work, the in vivo and in vitro activities of a new oxadiazole (LMM11) were evaluated against C. krusei. The minimum inhibitory concentration ranged from 32 to 64 μg/mL with a significant reduction in the colony forming unit (CFU) count (~3 log 10). LMM11 showed fungicidal effect, similar to amphotericin, reducing the viable cell number (>99.9%) in the time-kill curve. Yeast cells presented morphological alterations and inactive metabolism when treated with LMM11. This compound was also effective in decreasing C. krusei replication inside and outside macrophages. A synergistic effect between fluconazole and LMM11 was observed. In vivo treatment with the new oxadiazole led to a significant reduction in CFU (0.85 log 10). Furthermore, histopathological analysis of the treated group exhibited a reduction in the inflammatory area. Taken together, these results indicate that LMM11 is a promising candidate for the development of a new antifungal agent for the treatment of infections caused by resistant Candida species such as C. krusei.

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Section: Discussionmentioning

confidence: 99%

Promising antifungal activity of new oxadiazole against Candida krusei

et al. 2020

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“…This work reports the antifungal effects of these two oxadiazoles against Paracoccidioides spp., presenting an inhibition profile with MIC values between 1 and 32 μg/mL. Several studies have used the in silico approach to identify compounds for PCM treatment [16, 20, 25, 30, 35, 37]. The MIC values for these compounds was always similar to oxadiazoles.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, two homoserine dehydrogenase inhibitors demonstrated antifungal activity (MIC values 32–64 μg/mL) [25]. This group also synthetized 4-methoxy-naphthalene derivatives with antifungal activity against Paracoccidioides spp.…”

Section: Discussionmentioning

confidence: 99%

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Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Rodrigues-Vendramini¹,

Faria²,

Arita³

et al. 2019

PLoS Negl Trop Dis

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Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 μg/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (�2 log 10) on the 5 th and 7 th days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (�1 log 10). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies.

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“…Recently, 3 thioredoxin reductase inhibitors were selected by virtual screening with antifungal activity against Paracoccidioides spp., with MICs of 8 to 32 mg/liter (28). Furthermore, two compounds (HS1 and HS2) have been identified as homoserine dehydrogenase inhibitors showing antifungal activity (32 to 64 mg/liter) against P. brasiliensis (29). A Brazilian medicinal plant called Schinus terebinthifolius presented inhibitory activity against isolates Pb18 and Pb01, with MICs of 62.5 to 250 mg/liter (30).…”

Section: Discussionmentioning

confidence: 99%

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

Rodrigues-Vendramini

Marschalk

Toplak

et al. 2019

Antimicrob Agents Chemother

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Paracoccidioidomycosis (PCM), caused by Paracoccidioides, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics testing to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacological criteria (adsorption, distribution, metabolism, excretion, and toxicity) and was therefore used in in vitro experiments. Here we demonstrate that CP1 binds with a dissociation constant of 64 ± 1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity, with a 50% inhibitory concentration (IC50) of 47 ± 5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with a lower inflammatory response and is thus a promising candidate and lead structure for the development of drugs useful in PCM treatment.

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Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

Cited by 17 publications

References 54 publications

Promising antifungal activity of new oxadiazole against Candida krusei

Promising antifungal activity of new oxadiazole against Candida krusei

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

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