CHARACTERIZATION OF NUTRIENT UPTAKE MECHANISMS OF RESISTANT BACTERIA AND SEARCH FOR INHIBITORS USING BIOINFORMATICS
DOI:
https://doi.org/10.24933/rep.v8i1.450Keywords:
In silico analysis, Antibiotic Resistance, Nutrient transport, Molecular Docking, Targeted therapyAbstract
Acinetobacter baumannii and Klebsiella pneumoniae are gram-negative pathogens known for their antibiotic resistance, employing mechanisms of cellular communication and nutrient uptake mediated by ABC transporters. The substrate-binding proteins (SBPs) of these transporters play a crucial role in transport across the membrane and the absorption of nutrients, such as polyamines and taurine, which are essential for bacterial survival. This study aimed to characterize and predict the structures of SBPs that transport taurine and polyamines, as well as evaluate potential interactions with ligands and inhibitors. The FASTA sequences of PotD and TauA from A. baumannii, as well as PotD, PotF, and TauA from K. pneumoniae, were obtained from databases and analyzed using specific software to predict structure and interactions. Molecular docking performed on three-dimensional models of the proteins revealed favorable free energy for the binding of the proteins to their respective ligands, corroborating data from the literature; in particular, PotF from K. pneumoniaewas identified as a dual transporter of putrescine and spermidine. Additional tests showed that vigabatrin and GABA have the potential to interact with the TauA proteins, while cystamine was found to interact with PotD from A. baumannii. These results highlight the feasibility of using these molecules as targets to inhibit nutrient uptake in resistant bacteria, paving the way for the development of new antimicrobials. Identifying these interactions may open new avenues for treating infections caused by these pathogens, contributing to more effective therapeutic strategies in combating bacterial resistance.
Downloads
References
ALAM, A.; LOCHER, K. P. Structure and Mechanism of Human ABC Transporters. Annual Review of Biophysics, v. 52, p. 275-300, 2023. https://doi.org/10.1146/annurev-biophys-111622-091232 ALTMAN, R. B. A curriculum for bioinformatics: the time is ripe. Bioinformatics (Oxford, England), v. 14, n. 7, p. 549–550, 1998. https://doi.org/10.1093/bioinformatics/14.7.549 ALTSCHUL,S. F.; MADDEN, T. L.; SCHÄFFER, A. A.; ZHANG, J.; ZHANG, A.; MILLER, W.; LIPMAN, D. J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Research ̧v. 25, p. 3389-3402, 1997. https://doi.org/10.1093/nar/25.17.3389 ALMAGRO A., J. J. et al. SignalP 5.0 improves signal peptide predictions using deep neural networks. Nature biotechnology, v. 37, n. 4, p. 420–423, 2019. https://doi.org/10.1038/s41587-019-0036-z ARAUJO, F. T., BOLANOS-GARCIA, V. M., PEREIRA, C. T., SANCHES, M., OSHIRO, E. E., FERREIRA, R. C. C., CHIGARDZE, D. Y., BARBOSA, J. A. G., FERREIRA, L. C. S., BENEDETTI, C. E., BLUNDELL, T. L., BALAN, A. Structural and physiological analyses of the alkanesulphonatebinding protein (SsuA) of the citrus pathogen Xanthomonas citri. Brasília: PLoS One. v. 8, p. 1-14, 2013. https://doi.org/10.1371/journal.pone.0080083 BARTAL, C. ; ROLSTON, K. VI; NESHER, L. Carbapenem-resistant Acinetobacter baumannii: colonization, infection and current treatment options. Infectious diseases and therapy, v. 11, n. 2, p. 683-694, 2022. https://doi.org/10.1007/s40121-022-00597-w BERNTSSON, R. P., SMITS, S. H. J., SCHMITT, L., SLOTBOOM, D., POOLMAN, B. Structural classification of substrate-binding proteins. Düsseldorf: FEBS Letters, v. 584, p. 2606-2617, 2010. https://doi.org/10.1016/j.febslet.2010.04.043 BURNS, M. R. et al. Amino acid/spermine conjugates: polyamine amides as potent spermidine uptake inhibitors. Journal of medicinal chemistry, v. 44, n. 22, p. 3632-3644, 2001. https://doi.org/10.1021/jm0101040 CREMONESI, A.S.; DE LA TORRE, L.I.; DEGENHARDT, M.F.S.; MUNIZ,G.S.V.; LAMY, V.T.; OLIVEIRA, C.L.P. BALAN, A. The citrus plant pathogen Xanthomonas citri has a dual polyamine-binding protein. Archives of Biochemistry and Biophysics, v. 28, p. 1-12, 2021. https://doi.org/10.1016/j.bbrep.2021.101171 DAWSON, R. J.,; LOCHER, K. P. (). Structure of a bacterial multidrug ABC transporter. Nature, v. 443(7108), p. 180–185, 2006. https://doi.org/10.1038/nature05155 DIENSTMANN, R. et al. Avaliação fenotípica da enzima Klebsiella pneumoniae carbapenemase (KPC) em Enterobacteriaceae de ambiente hospitalar. Jornal Brasileiro de Patologia e Medicina Laboratorial, v. 46, p. 23-27, 2010. https://doi.org/10.1590/S1676-24442010000100005 GOODSWEN, S. J.; KENNEDY, P. J.; ELLIS, J. T. A guide to in silico vaccine discovery for eukaryotic pathogens. Briefings in bioinformatics, 24 out. 2012. https://doi.org/10.1093/bib/bbs066 GUEDES, I. A. et al. New machine learning and physics-based scoring functions for drug discovery. Scientific reports, v. 11, n. 1, p. 3198, 2021. https://doi.org/10.1038/s41598-021-82410-1 GUERRA, J. V. S et al. KVFinder-web: a web-based application for detecting and characterizing biomolecular cavities. Nucleic Acids Research, v. 51, n. W1, p. W289-W297, 2023. https://doi.org/10.1093/nar/gkad324 GUNA, A.; HEDGE, R. S. Transmembrane Domain Recognition during Membrane Protein Biogenesis and Quality Control. Current Biology Review, v.28, 2018. DOI: https://doi.org/10.1016/j.cub.2018.02.004 HOET, P. H. et al. Kinetics and cellular localisation of putrescine uptake in human lung tissue. Thorax, v. 48, n. 12, p. 1235-1241, 1993. https://doi.org/10.1136/thx.48.12.1235 IGARASHI, K.; KASHIWAGI, K. Polyamines: mysterious modulators of cellular functions. Biochemical and biophysical research communications, v. 271, n. 3, p. 559-564, 2000. https://doi.org/10.1006/bbrc.2000.2601 JONES, P. M.; GEORGE, A. M. Mechanism of the ABC transporter ATPase domains: catalytic models and the biochemical and biophysical record. Critical reviews in biochemistry and molecular biology, v. 48, n. 1, p. 39-50, 2013. DOI: https://doi.org/10.3109/10409238.2012.735644 KROGH, A. et al. Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. Journal of molecular biology, v. 305, n. 3, p. 567-580, 2001. https://doi.org/10.1006/jmbi.2000.4315 LARKIN, M. A. et al. Clustal W and Clustal X version 2.0. bioinformatics, v. 23, n. 21, p. 2947-2948, 2007. https://doi.org/10.1093/bioinformatics/btm404 LETUNIC I., SUPRIYA K., PEER B. SMART: recent updates, new developments and status in 2020. Nucleic Acids Research, v. 49, 2021. https://doi.org/10.1093/nar/gkaa937 LYBRAND, T. P. “Ligand-protein docking and rational drug design.” Current opinion in structural biology vol. 5,2 (1995): 224-8. doi:10.1016/0959-440x(95)80080-8 MARIANI, V. et al. lDDT: a local superposition-free score for comparing protein structures and models using distance difference tests. Bioinformatics, v. 29, n. 21, p. 2722-2728, 2013 .https://doi.org/10.1093/bioinformatics/btt473 MCGUFFIN, L. J.; BRYSON, Kevin; JONES, David T. The PSIPRED protein structure prediction server. Bioinformatics, v. 16, n. 4, p. 404-405, 2000. https://doi.org/10.1093/bioinformatics/16.4.404 MIRDITA, M. et al. ColabFold: making protein folding accessible to all. Nature methods, v. 19, n. 6, p. 679-682, 2022. https://doi.org/10.1038/s41592-022-01488-1 NISHIKAWA, M., SHEN, L.,; OGAWA, K. Taurine dioxygenase (tauD)-independent taurine assimilation in Escherichia coli. Microbiology (Reading, England), v. 164, n. 11, p. 1446–1456, 2018. https://doi.org/10.1099/mic.0.000723 PEREIRA, C. T. Estudos funcionais e estruturais sobre o transportador do tipo ABC de sulfato em Xanthomonas citri. 2017. Tese (Doutorado em Genética e Biologia Molecular) - Instituto de Biologia da Universidade Estadual de Campinas, São Paulo, 2017. RASMUSSEN, R. N. et al. Interaction of GABA-mimetics with the taurine transporter (TauT, Slc6a6) in hyperosmotic treated Caco-2, LLC-PK1 and rat renal SKPT cells. European Journal of Pharmaceutical Sciences, v. 82, p. 138-146, 2016 https://doi.org/10.1016/j.ejps.2015.11.020 RIBEIRO, E. C. R; DE OLIVEIRA SANTOS, M.; DE SOUSA, Georgette Carnib. Superbactéria: Os principais mecanismos e medicamentos de resistência bacteriana. REVISTA DA FAESF, v. 6, n. 3, 2023. https://doi.org/10.58969/25947125.6.3.2022.170 SALAMOV, V. S. A.; SOLOVYEVAND, A. Automatic annotation of microbial genomes and metagenomic sequences. Metagenomics and its applications in agriculture, biomedicine and environmental studies. Hauppauge: Nova Science Publishers, p. 61-78, 2011. SAMPAIO, A. et al. The periplasmic binding protein NrtT affects xantham gum production and pathogenesis in Xanthomonas citri. FEBS open bio, v. 7, n. 10, p. 1499-1514, 2017. https://doi.org/10.1002/2211-5463.12281
SANTANA, C. A. et al. GRaSP: a graph-based residue neighborhood strategy to predict binding sites. Bioinformatics, v. 36, n. Supplement_2, p. i726-i734, 2020. https://doi.org/10.1093/bioinformatics/btaa805 SILVA, K.M.; FIGUEIREDO, N.G.; CREMONESI, A.S. Use of Bioinformatics Techniques in the Characterization of Genes and Proteins Involved in the Transport of Polyamines from Staphylococcus Genus. JSM Bioinformatics, Genomics and Proteomics, v. 6(1), 2023. https://doi.org/10.47739/2576-1102.bioinformatics.1041 STOJOWSKA-SWĘDRZYŃSKA, K. et al. Antibiotic heteroresistance in Klebsiella pneumoniae. International Journal of Molecular Sciences, v. 23, n. 1, p. 449, 2021. https://doi.org/10.3390/ijms23010449 VAN DER PLOEG, J. R. et al. Involvement of CysB and Cbl regulatory proteins in expression of the tauABCD operon and other sulfate starvation-inducible genes in Escherichia coli. Journal of bacteriology, v. 179, n. 24, p. 7671-7678, 1997. https://doi.org/10.1128/jb.179.24.7671-7678.1997 VIEIRA, P. B.; PICOLI, S. U. Acinetobacter Baumannii multirresistente: aspectos clínicos e epidemiológicos. Revista Brasileira de Ciências da Saúde, v. 19., p. 151-6, 2015. DOI:10.4034/RBCS.2015.19.02.10 VON HEIJNE, G. The signal peptide. The Journal of membrane biology, v. 115, p. 195-201, 1990. https://doi.org/10.1007/bf01868635 QU, F., ELOMARI, K., WAGNER, A., DE SIMONE, A.,; BEIS, K. Desolvation of the substrate-binding protein TauA dictates ligand specificity for the alkanesulfonate ABC importer TauABC. The Biochemical journal, v. 476, n. 23, p. 3649–3660, 2019. https://doi.org/10.1042/bcj20190779 WISHART, D. S., FEUNANG, Y. D., GUO, A. C., LO, E. J., MARCU, A., GRANT, J. R., SAJED, T., JOHNSON, D., LI, C., SAYEEDA, Z., ASSEMPOUR, N., IYNKKARAN, I., LIU, Y., MACIEJEWSKI, A., GALE, N., WILSON, A., CHIN, L., CUMMINGS, R., LE, D., PON, A., … WILSON, M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic acids research. v. 46, e. 1, p. D1074-D1082, 2018. https://doi.org/10.1093/nar/gkx1037
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Aline Sampaio Cremonesi, Geovana Almeida Carneiro, Heber da Silva Antonio, Ana Carolina Chiou Nascimento
This work is licensed under a Creative Commons Attribution 4.0 International License.
Autores que publicam nesta revista concordam com os seguintes termos:
a) Autores mantém os direitos autorais e concedem à revista o direito de primeira publicação, com o trabalho simultaneamente licenciado sob a Licença Creative Commons Attribution que permite o compartilhamento do trabalho com reconhecimento da autoria e publicação inicial nesta revista.
b) Autores têm autorização para assumir contratos adicionais separadamente, para distribuição não-exclusiva da versão do trabalho publicada nesta revista (ex.: publicar em repositório institucional ou como capítulo de livro), com reconhecimento de autoria e publicação inicial nesta revista.
c) Autores têm permissão e são estimulados a publicar e distribuir seu trabalho online (ex.: em repositórios institucionais ou na sua página pessoal) a qualquer ponto antes ou durante o processo editorial, já que isso pode gerar alterações produtivas, bem como aumentar o impacto e a citação do trabalho publicado (Veja O Efeito do Acesso Livre).
