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Antifungal Activity of ToAP2D Peptide Against Sporothrix globosa

ABSTRACT: Improving clinical efficacy and reducing treatment time have been the focus of sporotrichosis therapy. Antimicrobial peptides ToAP2A, ToAP2C, and ToAP2D were synthesized on the basis of ToAP2 (AP02759), a peptide derived from the antimicrobial peptide database by the database filtering technology, and their physicochemical characteristics were analyzed. Compared with template peptide ToAP2, the modified peptides had much shorter length, lower molecular weight but significantly greater stability, which in return resulted in increases in the aliphatic index, hydrophilicity, and protein binding ability. Here, we show that the three derived peptides inhibit the growth of Sporothrix globosa, among which ToAP2D had the strongest anti-fungal activity. ToAP2D showed good serum stability without acute toxicity. The ToAP2D treatment inhibited the growth of S. globosa and enhanced apoptosis, which was evidenced by the upregulation of apoptosis-related protein caspase-3. The scanning electron microscopy analysis revealed deformation and rupture of S. globosa. The levels of mitochondrial membrane potential were decreased and that of the reactive oxygen species (ROS) were increased in S. globosa upon ToAP2D treatment. Moreover, ToAP2D activated metacaspase. In the in vivo study, we further demonstrated that ToAP2D inhibited the S. globosa infection of mice footpads, and its efficiency was nearly comparable to itraconazole. In summary, our results suggest that antimicrobial peptide ToAP2D has the potential for sporotrichosis therapy.

SUBMITTER: Yan T

PROVIDER: S-EPMC8566951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The dimorphic fungus Sporothrix globosa is the predominant etiologic agent causing sporotrichosis in China, particularly in the northeast. It has been demonstrated that the incubation temperature and growth phase can influence in vitro antifungal susceptibility profiles of S. schenckii sensu stricto and S. brasiliensis (sibling species of S. globosa). Few studies have reported on the antifungal susceptibility of S. globosa, especially using large numbers of isolates. In this study, we assessed the susceptibility of 80 isolates of S. globosa originating from Jilin Province, northeastern China, to six antifungal agents (itraconazole, terbinafine, voriconazole, posaconazole, fluconazole, and amphotericin B), at varying incubation temperatures and in different fungal growth phases. The isolates were most sensitive to terbinafine (geometric mean [GM] of the minimum inhibitory concentration [MIC]: 0.0356 μg/ml for the mycelial phase at 30 °C, 0.0332 μg/ml for the mycelial phase at 35 °C, and 0.031 μg/ml for the yeast phase, respectively), followed by posaconazole (GM of the MIC: 4.2501 μg/ml for the mycelial phase at 30 °C, 1.4142 μg/ml for the mycelial phase at 35 °C, and 0.7195 μg/ml for the yeast phase, respectively) and itraconazole (GM of the MIC: 6.8448 μg/ml for the mycelial phase at 30 °C, 3.1383 μg/ml for the mycelial phase at 35 °C, and 1.0263 μg/ml for the yeast phase, respectively). The isolates were relatively resistant to fluconazole (GM of the MIC: 76.7716 μg/ml for the mycelial phase at 30 °C, 66.2570 μg/ml for the mycelial phase at 35 °C, and 24.4625 μg/ml for the yeast phase, respectively) and voriconazole (GM of the MIC: 26.2183 μg/ml for the mycelial phase at 30 °C, 13.6895 μg/ml for the mycelial phase at 35 °C, and 1.3899 μg/ml for the yeast phase, respectively). For all the tested azole drugs, the MICs at 30 °C were significantly higher than those at 35 °C (P < 0.001); for all agents except terbinafine, the MICs of S. globosa in the yeast phase were significantly lower than those of the strains in the mycelial phase (P < 0.001). These results show that the sensitivities of S. globosa to antifungal compounds are dependent on incubation temperature and growth phase. To the best of our knowledge, this is the largest study of antifungal susceptibility of S. globosa isolates reported to date. To establish epidemiological cutoff values for S. globosa, further antifungal susceptibility testing studies by independent laboratories located in different regions and using uniform conditions are required.

Project description:Abstract Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM Objectives Sporotrichosis is the leading subcutaneous mycosis caused by the Sporothrix (S.) schenckii complex. S. globosa is the causative organism of fixed sporotrichosis in Korea. The preferred regimen of cutaneous sporotrichosis is itraconazole for 3-6 months, however, there were few studies for recalcitrant sporotrichosis. Methods In 2018, we performed a histological examination of a patient who suffered sporotrichosis for 3 years and cultured part of the specimen. Despite various regimens for years, improvement and exacerbation were repeated, so we took another skin biopsy and cultured it in 2021. Isolates from the 2018 and 2021 lesions were identified as S. globosa by ribosomal DNA ITS sequencing (GenBank accession number: MH499862 and MH499863). The in vitro antifungal sensitivity tests were performed by broth microdilution method according to CLSI M38-A2 guidelines or Sensititre YeastOne® manufacturer's instructions. They were incubated at 30°C in a non-CO2 incubator for 7 days. Results In 2018, histologically, we observed chronic inflammatory granuloma comprising lymphocytes, histiocytes, and giant cells, and several spores with periodic acid-Schiff (PAS) staining. Microscopic findings and ITS sequences of rRNA gene were identical with S. globosa. The antifungal susceptibility profile in 2018 revealed sensitive to terbinafine (0.125 μg/ml), and moderate to high MIC values for amphotericin B (2 μg/ml), itraconazole (>16 μg/ml), voriconazole (>16 μg/ml), and echinocandins (>16 μg/ml). Treatment with terbinafine, itraconazole, or amphotericin B, the skin lesions were partially improved, but were not cured. In 2021, we took another skin biopsy and culture specimen. Histopathological and mycological examination results were the same as before. The antifungal susceptibility profile revealed sensitive to itraconazole (0.5/ml), and high MIC for others. Clinically, skin lesions were not improved with the use of itraconazole 200 mg/d. Itraconazole 400 mg/d with local heating induced moderate improvement. There was no evidence of immune deficiency. Conclusion We experienced recalcitrant sporotrichosis that did not respond to itraconazole and terbinafine, and the sensitivity of antifungal was changed. In this case, the combination treatment including local heating, saturated KI may be considered, and frequent antifungal susceptibility tests are needed.

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Antifungal Activity of ToAP2D Peptide Against Sporothrix globosa

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