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Article

Behind the Curtain: In Silico and In Vitro Experiments Brought to Light New Insights into the Anticryptococcal Action of Synthetic Peptides

by
Tawanny K. B. Aguiar
1,
Nilton A. S. Neto
1,
Romério R. S. Silva
1,
Cleverson D. T. Freitas
1,
Felipe P. Mesquita
2,
Luciana M. R. Alencar
3,
Ralph Santos-Oliveira
4,5,
Gustavo H. Goldman
6 and
Pedro F. N. Souza
1,2,*
1
Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, CE, Brazil
2
Drug Research and Development Center, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza 60430-275, CE, Brazil
3
Department of Physics, Laboratory of Biophysics and Nanosystems, Federal University of Maranhão, São Luís 65080-805, MA, Brazil
4
Laboratory of Nanoradiopharmaceuticals and Radiopharmacy, Zona Oeste State University, Rio de Janeiro 23070-200, RJ, Brazil
5
Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Rio de Janeiro 21941-906, RJ, Brazil
6
Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo 14040-903, SP, Brazil
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(1), 153; https://doi.org/10.3390/antibiotics12010153
Submission received: 16 December 2022 / Revised: 8 January 2023 / Accepted: 10 January 2023 / Published: 11 January 2023
(This article belongs to the Special Issue Computational Approaches in Discovery & Design of Antimicrobial Peptides)
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Abstract

Cryptococcus neoformans is the pathogen responsible for cryptococcal pneumonia and meningitis, mainly affecting patients with suppressed immune systems. We have previously revealed the mechanism of anticryptococcal action of synthetic antimicrobial peptides (SAMPs). In this study, computational and experimental analyses provide new insights into the mechanisms of action of SAMPs. Computational analysis revealed that peptides interacted with the PHO36 membrane receptor of C. neoformans. Additionally, ROS (reactive oxygen species) overproduction, the enzymes of ROS metabolism, interference in the ergosterol biosynthesis pathway, and decoupling of cytochrome c mitochondrial membrane were evaluated. Three of four peptides were able to interact with the PHO36 receptor, altering its function and leading to ROS overproduction. SAMPs-treated C. neoformans cells showed a decrease in scavenger enzyme activity, supporting ROS accumulation. In the presence of ascorbic acid, an antioxidant agent, SAMPs did not induce ROS accumulation in C. neoformans cells. Interestingly, two SAMPs maintained inhibitory activity and membrane pore formation in C. neoformans cells by a ROS-independent mechanism. Yet, the ergosterol biosynthesis and lactate dehydrogenase activity were affected by SAMPs. In addition, we noticed decoupling of Cyt c from the mitochondria, which led to apoptosis events in the cryptococcal cells. The results presented herein suggest multiple mechanisms imposed by SAMPs against C. neoformans interfering in the development of resistance, thus revealing the potential of SAMPs in treating infections caused by C. neoformans.
Keywords: redox system; Cryptococcus neoformans; ROS metabolism; ergosterol; synthetic antimicrobial peptides redox system; Cryptococcus neoformans; ROS metabolism; ergosterol; synthetic antimicrobial peptides

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MDPI and ACS Style

Aguiar, T.K.B.; Neto, N.A.S.; Silva, R.R.S.; Freitas, C.D.T.; Mesquita, F.P.; Alencar, L.M.R.; Santos-Oliveira, R.; Goldman, G.H.; Souza, P.F.N. Behind the Curtain: In Silico and In Vitro Experiments Brought to Light New Insights into the Anticryptococcal Action of Synthetic Peptides. Antibiotics 2023, 12, 153. https://doi.org/10.3390/antibiotics12010153

AMA Style

Aguiar TKB, Neto NAS, Silva RRS, Freitas CDT, Mesquita FP, Alencar LMR, Santos-Oliveira R, Goldman GH, Souza PFN. Behind the Curtain: In Silico and In Vitro Experiments Brought to Light New Insights into the Anticryptococcal Action of Synthetic Peptides. Antibiotics. 2023; 12(1):153. https://doi.org/10.3390/antibiotics12010153

Chicago/Turabian Style

Aguiar, Tawanny K. B., Nilton A. S. Neto, Romério R. S. Silva, Cleverson D. T. Freitas, Felipe P. Mesquita, Luciana M. R. Alencar, Ralph Santos-Oliveira, Gustavo H. Goldman, and Pedro F. N. Souza. 2023. "Behind the Curtain: In Silico and In Vitro Experiments Brought to Light New Insights into the Anticryptococcal Action of Synthetic Peptides" Antibiotics 12, no. 1: 153. https://doi.org/10.3390/antibiotics12010153

APA Style

Aguiar, T. K. B., Neto, N. A. S., Silva, R. R. S., Freitas, C. D. T., Mesquita, F. P., Alencar, L. M. R., Santos-Oliveira, R., Goldman, G. H., & Souza, P. F. N. (2023). Behind the Curtain: In Silico and In Vitro Experiments Brought to Light New Insights into the Anticryptococcal Action of Synthetic Peptides. Antibiotics, 12(1), 153. https://doi.org/10.3390/antibiotics12010153

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