TY - JOUR AU - Muhammad, Abubakar AU - Sarkadi, Zsuzsa AU - Mazumder, Agnisrota AU - Ait, Saada Anissia AU - van, Emden Thomas AU - Capella, Matias AU - Fekete, Gergely AU - Suma, Sreechakram Vishnu N. AU - Al-Sady, Bassem AU - Lambert, Sarah A. E. AU - Papp, Balázs AU - Barrales, Ramon Ramos AU - Braun, Sigurd TI - A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 52 PY - 2024 IS - 22 SP - 13665 EP - 13689 PG - 25 SN - 0305-1048 DO - 10.1093/nar/gkae1024 UR - https://m2.mtmt.hu/api/publication/35619924 ID - 35619924 N1 - Funding Agency and Grant Number: Agence Nationale de la Recherche; Foundation ARC Funding text: We thank members of the Braun lab, A. Ladurner and S. Hake for fruitful discussions during the study. We thank R. Allshire, E. Bayne, J. Kanoh and M. Knop for strains and plasmids. We thank S. Lall (Life Science Editors) for editorial assistance and critical comments on the manuscript. Furthermore, we thank S. Fischer-Burkart, M. Bingel, T. Uhlig, S. Schau ss and P. Molis for technical assistance. Schemes in figures were created with BioRender.com. A.A.S. was supported by a postdoctoral fellowship from the Foundation ARC. AB - Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces pombe. Using quantitative measures, iterative genetic screening and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. However, most other mutants exhibited distinct qualitative and quantitative profiles that indicate heterochromatin domain-specific functions, as seen for example for metabolic pathways affecting primarily subtelomere silencing. Moreover, similar phenotypic profiles revealed shared functions for subunits within complexes. We further discovered that the uncharacterized protein Dhm2 plays a crucial role in heterochromatin maintenance, affecting the inheritance of H3K9 methylation and the clonal propagation of the repressed state. Additionally, Dhm2 loss resulted in delayed S-phase progression and replication stress. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity. [GRAPHICS] . LA - English DB - MTMT ER - TY - JOUR AU - Koncz, Mihály AU - Stirling, Tamás AU - Hadj Mehdi, Hiba AU - Méhi, Orsolya Katinka AU - Eszenyi, Bálint Dénes AU - Asbóth, András AU - Apjok, Gábor AU - Tóth, Ákos AU - Orosz, László AU - Vásárhelyi, Bálint Márk AU - Ari, Eszter AU - Daruka, Lejla AU - Polgár, Tamás Ferenc AU - Schneider, György AU - Zalokh, Sif Aldin AU - Számel, Mónika AU - Fekete, Gergely AU - Bohár, Balázs AU - Nagy Varga, Karolina AU - Visnyovszki, Ádám AU - Székely, Edit AU - Licker, Monica-Sorina AU - Izmendi, Oana AU - Costache, Carmen AU - Gajic, Ina AU - Lukovic, Bojana AU - Molnár, Szabolcs AU - Szőcs-Gazdi, Uzonka Orsolya AU - Bozai, Csilla AU - Indreas, Marina AU - Kristóf, Katalin AU - Van der Henst, Charles AU - Breine, Anke AU - Pál, Csaba AU - Papp, Balázs AU - Kintses, Bálint TI - Genomic surveillance as a scalable framework for precision phage therapy against antibiotic-resistant pathogens JF - CELL J2 - CELL VL - 187 PY - 2024 IS - 21 SP - 5901 EP - 5918.e28 PG - 47 SN - 0092-8674 DO - 10.1016/j.cell.2024.09.009 UR - https://m2.mtmt.hu/api/publication/35422693 ID - 35422693 AB - Phage therapy is gaining increasing interest in the fight against critically antibiotic-resistant nosocomial pathogens. However, the narrow host range of bacteriophages hampers the development of broadly effective phage therapeutics and demands precision approaches. Here, we combine large-scale phylogeographic analysis with high-throughput phage typing to guide the development of precision phage cocktails targeting carbapenem-resistant Acinetobacter baumannii, a top-priority pathogen. Our analysis reveals that a few strain types dominate infections in each world region, with their geographical distribution remaining stable within 6 years. As we demonstrate in Eastern Europe, this spatiotemporal distribution enables preemptive preparation of region-specific phage collections that target most local infections. Finally, we showcase the efficacy of phage cocktails against prevalent strain types using in vitro and animal infection models. Ultimately, genomic surveillance identifies patients benefiting from the same phages across geographical scales, thus providing a scalable framework for precision phage therapy. LA - English DB - MTMT ER - TY - JOUR AU - Turek, Cezary AU - Olbei, Marton AU - Stirling, Tamás AU - Fekete, Gergely AU - Tasnádi, Ervin Áron AU - Gul, Leila AU - Bohár, Balázs AU - Papp, Balázs AU - Jurkowski, Wiktor AU - Ari, Eszter TI - mulea - an R package for enrichment analysis using multiple ontologies and empirical FDR correction JF - BMC BIOINFORMATICS J2 - BMC BIOINFORMATICS VL - 25 PY - 2024 IS - 1 PG - 13 SN - 1471-2105 DO - 10.1186/s12859-024-05948-7 UR - https://m2.mtmt.hu/api/publication/34718081 ID - 34718081 AB - Traditional gene set enrichment analyses are typically limited to a few ontologies and do not account for the interdependence of gene sets or terms, resulting in overcorrected p-values. To address these challenges, we introduce mulea, an R package offering comprehensive overrepresentation and functional enrichment analysis. mulea employs an innovative empirical false discovery rate (eFDR) correction method, specifically designed for interconnected biological data, to accurately identify significant terms within diverse ontologies. mulea expands beyond traditional tools by incorporating a wide range of ontologies, encompassing Gene Ontology, pathways, regulatory elements, genomic locations, and protein domains. This flexibility enables researchers to tailor enrichment analysis to their specific questions, such as identifying enriched transcriptional regulators in gene expression data or overrepresented protein domains in protein sets. To facilitate seamless analysis, mulea provides gene sets (in standardised GMT format) for 27 model organisms, covering 16 databases and various identifiers resulting in almost 900 files. Additionally, the muleaData ExperimentData Bioconductor package simplifies access to these pre-defined ontologies. Finally, mulea's architecture allows for easy integration of user-defined ontologies, expanding its applicability across diverse research areas. Availability and Implementation: Software for the tools demonstrated in this article is available as an R package on GitHub: https://github.com/ELTEbioinformatics/mulea. LA - English DB - MTMT ER - TY - JOUR AU - Apjok, Gábor AU - Számel, Mónika AU - Christodoulou, Chryso AU - Seregi, Viktória AU - Vásárhelyi, Bálint Márk AU - Stirling, Tamás AU - Eszenyi, Bálint Dénes AU - Sári, Tóbiás AU - Vidovics, Fanni AU - Nagrand, Erika AU - Kovács, Dorina AU - Szili, Petra AU - Lantos, Ildikó Ilona AU - Méhi, Orsolya Katinka AU - Jangir, Pramod Kumar AU - Herczeg, Róbert AU - Gálik, Bence AU - Urbán, Péter AU - Gyenesei, Attila AU - Draskovits, Gábor AU - Nyerges, Ákos AU - Fekete, Gergely AU - Bodai, László AU - Zsindely, Nóra AU - Dénes, Béla AU - Yosef, Ido AU - Qimron, Udi AU - Papp, Balázs AU - Pál, Csaba AU - Kintses, Bálint TI - Characterization of antibiotic resistomes by reprogrammed bacteriophage-enabled functional metagenomics in clinical strains JF - NATURE MICROBIOLOGY J2 - NAT MICROBIOL VL - 8 PY - 2023 IS - 3 SP - 410 EP - 423 PG - 14 SN - 2058-5276 DO - 10.1038/s41564-023-01320-2 UR - https://m2.mtmt.hu/api/publication/33634821 ID - 33634821 N1 - Funding Agency and Grant Number: National Laboratory of Biotechnology Grants [NKFIH-871-3/2020, 2022-2.1.1-NL-2022-00008]; European Union [754432]; European Research Council [648364, 862077]; National Research, Development and Innovation Office grant [FK-135245, FK-124254]; National Research, Development and Innovation Office; Ministry for Innovation and Technology [KKP 129814, 126506]; New National Excellence Program of the Ministry of Human Capacities [UNKP-20-5-SZTE-654, UNKP-21-5-SZTE-579]; New National Excellence Program of the Ministry for Innovation and Technology - National Research, Development and Innovation Fund [UNKP-20-3 -SZTE-452]; Doctoral Student Scholarship Program of the Co-Operative Doctoral Program of the Ministry of Innovation and Technology - National Research, Development and Innovation Fund [KDP-17-4/ PALY-2021, C992025]; European Union's Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant [754432]; Polish Ministry of Science and Higher Education; National Academy of Scientist Education Program of the National Biomedical Foundation under Hungarian Ministry of Culture and Innovation; National Laboratory for Health Security [RRF-2.3.1-212022-00006, GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020, GINOP-2.3.2-15-2016-00035]; Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences [BO/352/20, BO/00303/19/8]; [GINOP-2.3.4-15-2020-00010]; [GINOP-2.3.1-20-2020-00001]; [BECOMING-2019-1-HU01-KA203-061251] Funding text: We thank D. Verma from the Department of Microbiology and B. Bhimrao of Ambedkar University, Lucknow, India for help with soil sample collection and NBA approval. This work was supported by National Laboratory of Biotechnology Grants NKFIH-871-3/2020 and 2022-2.1.1-NL-2022-00008 (B.K. and C.P.); the European Union's Horizon 2020 research and innovation programme under grant agreement no. 739593 (B.P. and B.K.); the European Research Council H2020-ERC-2014-CoG 648364-Resistance Evolution (C.P.) and H2020-ERC-2019-PoC 862077-Aware (C.P.); National Research, Development and Innovation Office grant FK-135245 (B.K.) and FK-124254 (O.M.); the National Research, Development and Innovation Office and the Ministry for Innovation and Technology under the `Frontline' Programme KKP 129814 and 126506 (B.P. and C.P.); the National Laboratory for Health Security RRF-2.3.1-212022-00006 (B.P.), GINOP-2.3.2-15-2016-00014 (EVOMER, C.P. and B.P.), GINOP-2.3.2-15-2016-00020 (MolMedEx TUMORDNS, C.P.), GINOP-2.3.2-15-2016-00035 (N.Z.); a Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences (BO/352/20 (B.K.), BO/00303/19/8 (O.M)); New National Excellence Program of the Ministry of Human Capacities (UNKP-20-5-SZTE-654 and UNKP-215-SZTE-579, B.K.); New National Excellence Program of the Ministry for Innovation and Technology funded by the National Research, Development and Innovation Fund (UNKP-20-3 -SZTE-452, G.A.); the Doctoral Student Scholarship Program of the Co-Operative Doctoral Program of the Ministry of Innovation and Technology financed by the National Research, Development and Innovation Fund (KDP-17-4/ PALY-2021, C992025, M.S.). R.H., B.G., P.U. and A.G. were supported by GINOP-2.3.4-15-2020-00010, GINOP-2.3.1-20-2020-00001, BECOMING-2019-1-HU01-KA203-061251, the European Union's Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement no. 754432 and the Polish Ministry of Science and Higher Education, from the financial resources for science in 2018-2023. This research work was conducted with the support of the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (D.K.). AB - Functional metagenomics is a powerful experimental tool to identify antibiotic resistance genes (ARGs) in the environment, but the range of suitable host bacterial species is limited. This limitation affects both the scope of the identified ARGs and the interpretation of their clinical relevance. Here we present a functional metagenomics pipeline called Reprogrammed Bacteriophage Particle Assisted Multi-species Functional Metagenomics (DEEPMINE). This approach combines and improves the use of T7 bacteriophage with exchanged tail fibres and targeted mutagenesis to expand phage host-specificity and efficiency for functional metagenomics. These modified phage particles were used to introduce large metagenomic plasmid libraries into clinically relevant bacterial pathogens. By screening for ARGs in soil and gut microbiomes and clinical genomes against 13 antibiotics, we demonstrate that this approach substantially expands the list of identified ARGs. Many ARGs have species-specific effects on resistance; they provide a high level of resistance in one bacterial species but yield very limited resistance in a related species. Finally, we identified mobile ARGs against antibiotics that are currently under clinical development or have recently been approved. Overall, DEEPMINE expands the functional metagenomics toolbox for studying microbial communities. LA - English DB - MTMT ER - TY - JOUR AU - Györkei, Ádám AU - Daruka, Lejla AU - Balogh, Dávid AU - Őszi, Erika AU - Magyar, Zoltán AU - Szappanos, Balázs AU - Fekete, Gergely AU - Fuxreiter, Mónika AU - Horváth, Péter AU - Pál, Csaba AU - Kintses, Bálint AU - Papp, Balázs TI - Proteome-wide landscape of solubility limits in a bacterial cell JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 12 PY - 2022 IS - 1 PG - 13 SN - 2045-2322 DO - 10.1038/s41598-022-10427-1 UR - https://m2.mtmt.hu/api/publication/32813213 ID - 32813213 N1 - Funding Agency and Grant Number: ELKH Biological Research Center Funding text: Open access funding provided by ELKH Biological Research Center. AB - Proteins are prone to aggregate when expressed above their solubility limits. Aggregation may occur rapidly, potentially as early as proteins emerge from the ribosome, or slowly, following synthesis. However, in vivo data on aggregation rates are scarce. Here, we classified the Escherichia coli proteome into rapidly and slowly aggregating proteins using an in vivo image-based screen coupled with machine learning. We find that the majority (70%) of cytosolic proteins that become insoluble upon overexpression have relatively low rates of aggregation and are unlikely to aggregate co-translationally. Remarkably, such proteins exhibit higher folding rates compared to rapidly aggregating proteins, potentially implying that they aggregate after reaching their folded states. Furthermore, we find that a substantial fraction (similar to 35%) of the proteome remain soluble at concentrations much higher than those found naturally, indicating a large margin of safety to tolerate gene expression changes. We show that high disorder content and low surface stickiness are major determinants of high solubility and are favored in abundant bacterial proteins. Overall, our study provides a global view of aggregation rates and hence solubility limits of proteins in a bacterial cell. LA - English DB - MTMT ER - TY - JOUR AU - Farkas, Zoltán AU - Kovács, Károly AU - Sarkadi, Zsuzsa AU - Kalapis, Dorottya AU - Fekete, Gergely AU - Birtyik, Fanni AU - Ayaydin, Ferhan AU - Molnár, Csaba AU - Horváth, Péter AU - Pál, Csaba AU - Papp, Balázs TI - Gene loss and compensatory evolution promotes the emergence of morphological novelties in budding yeast JF - NATURE ECOLOGY & EVOLUTION J2 - NAT ECOL EVOL VL - 6 PY - 2022 IS - 6 SP - 763 EP - 773 PG - 11 SN - 2397-334X DO - 10.1038/s41559-022-01730-1 UR - https://m2.mtmt.hu/api/publication/32803914 ID - 32803914 N1 - Funding Agency and Grant Number: 'Lendulet' program of the Hungarian Academy of Sciences [LP2009-013/2012, LP 2017 10/2020]; LENDULET-BIOMAG grant [2018-342]; Wellcome TrustWellcome Trust [WT 098016/Z/11/Z]; National Laboratory of Biotechnology [NKFIH-871-3/2020]; European Research CouncilEuropean Research Council (ERC)European Commission [H2020-ERC-2014-CoG 648364]; National Research, Development and Innovation Office Elvonal Program [KKP 126506, KKP 129814]; Economic Development and Innovation Operational Programme: European Regional Development Funds [GINOP-2.3.2-15-2016-00006, GINOP-2.3.2-15-2016-00037, GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020, GINOP-2.3.2-15-2016-00026]; European Union's Horizon 2020 research and innovation program [739593]; COMPASS-ERA PerMed H2020; CZI Deep Visual Proteomics; H2020-DiscovAir; ELKH-Excellence grant; Hungarian Academy of Sciences Postdoctoral Fellowship Program [Postdoc2014-85]; National Research, Development and Innovation OfficeNational Research, Development & Innovation Office (NRDIO) - Hungary [FK 128775, FK 128916]; Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences [BO/779/20]; New National Excellence Program of the Ministry of Human Capacities Bolyai+ [UNKP-20-5-SZTE-646, UNKP-21-5-SZTE-562] Funding text: The FRE-LacZ plasmid (YEpU-FTyZ) was a kind gift from J. Thorner. We thank Z. Bodi for informal discussions, K. Ambrus for her general technical assistance, E. Kotogany for her help in the flow-cytometry measurements and I. Kelemen-Valkony for her help in laser scanning confocal microscopy. Funding and grant sources are as follows: 'Lendulet' program of the Hungarian Academy of Sciences LP2009-013/2012 (B.P.); 'Lendulet' program of the Hungarian Academy of Sciences LP-2017-10/2020 (C.P.); LENDULET-BIOMAG grant 2018-342 (P.H.); Wellcome Trust WT 098016/Z/11/Z (B.P.); National Laboratory of Biotechnology grant NKFIH-871-3/2020 (C.P.); the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.); National Research, Development and Innovation Office Elvonal Program KKP 126506 (C.P.); National Research, Development and Innovation Office Elvonal Program KKP 129814 (B.P.); Economic Development and Innovation Operational Programme: European Regional Development Funds GINOP-2.3.2-15-2016-00006 (P.H.); Economic Development and Innovation Operational Programme: European Regional Development Funds GINOP-2.3.2-15-2016-00037 (P.H.); Economic Development and Innovation Operational Programme: European Regional Development Funds GINOP-2.3.2-15-2016-00014 (C.P., B.P.); Economic Development and Innovation Operational Programme: European Regional Development Funds GINOP-2.3.2-15-2016-00020 (C.P.); Economic Development and Innovation Operational Programme: European Regional Development Funds GINOP-2.3.2-15-2016-00026 (B.P., P.H.); the European Union's Horizon 2020 research and innovation program grant number 739593 (B.P., F.A.); COMPASS-ERA PerMed H2020 (P.H.); CZI Deep Visual Proteomics (P.H.); H2020-DiscovAir (P.H.); ELKH-Excellence grant (P.H.); Hungarian Academy of Sciences Postdoctoral Fellowship Program Postdoc2014-85 (K.K.); National Research, Development and Innovation Office FK 128775 (Z.F.); National Research, Development and Innovation Office FK 128916 (D.K.); Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences BO/779/20 (Z.F.); New National Excellence Program of the Ministry of Human Capacities Bolyai+, UNKP-20-5-SZTE-646 (Z.F.); and New National Excellence Program of the Ministry of Human Capacities Bolyai+, UNKP-21-5-SZTE-562 (Z.F.). LA - English DB - MTMT ER - TY - JOUR AU - Apjok, Gábor AU - Boross, Gábor AU - Nyerges, Ákos AU - Fekete, Gergely AU - Lázár, Viktória AU - Papp, Balázs AU - Pál, Csaba AU - Csörgő, Bálint TI - Corrigendum to: Limited evolutionary conservation of multidrug resistance and collateral sensitivity (vol 36, pg 1601, 2019) JF - MOLECULAR BIOLOGY AND EVOLUTION J2 - MOL BIOL EVOL VL - 38 PY - 2021 IS - 7 SP - 3029 EP - 3029 PG - 1 SN - 0737-4038 DO - 10.1093/molbev/msab116 UR - https://m2.mtmt.hu/api/publication/32106320 ID - 32106320 LA - English DB - MTMT ER - TY - JOUR AU - Kintses, Bálint AU - Jangir, Pramod Kumar AU - Fekete, Gergely AU - Számel, Mónika AU - Méhi, Orsolya Katinka AU - Spohn, Réka AU - Daruka, Lejla AU - Martins, Ana AU - Hosseinnia, A. AU - Gagarinova, A. AU - Kim, S. AU - Phanse, S. AU - Csörgő, Bálint AU - Györkei, Ádám AU - Ari, Eszter AU - Lázár, Viktória AU - Nagy, István AU - Babu, M. AU - Pál, Csaba AU - Papp, Balázs TI - Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 10 PY - 2019 IS - 1 PG - 13 SN - 2041-1723 DO - 10.1038/s41467-019-13618-z UR - https://m2.mtmt.hu/api/publication/31038930 ID - 31038930 N1 - Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary Department of Biochemistry, University of Regina, Regina, SK, Canada Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada Department of Genetics, Eötvös Loránd University, Budapest, Hungary Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Department of Microbiology and Immunology, University of California, San Francisco, United States Faculty of Biology, Technion – Israel Institute of Technology, Haifa, Israel Export Date: 6 January 2020 Correspondence Address: Kintses, B.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research CentreHungary; email: kintses.balint@brc.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary Department of Biochemistry, University of Regina, Regina, SK, Canada Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada Department of Genetics, Eötvös Loránd University, Budapest, Hungary Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Department of Microbiology and Immunology, University of California, San Francisco, United States Faculty of Biology, Technion – Israel Institute of Technology, Haifa, Israel Export Date: 23 January 2020 Correspondence Address: Kintses, B.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research CentreHungary; email: kintses.balint@brc.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary Department of Biochemistry, University of Regina, Regina, SK, Canada Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada Department of Genetics, Eötvös Loránd University, Budapest, Hungary Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Department of Microbiology and Immunology, University of California, San Francisco, United States Faculty of Biology, Technion – Israel Institute of Technology, Haifa, Israel Cited By :1 Export Date: 24 August 2020 Correspondence Address: Kintses, B.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research CentreHungary; email: kintses.balint@brc.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary Department of Biochemistry, University of Regina, Regina, SK, Canada Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada Department of Genetics, Eötvös Loránd University, Budapest, Hungary Sequencing Platform, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Department of Microbiology and Immunology, University of California, San Francisco, United States Faculty of Biology, Technion – Israel Institute of Technology, Haifa, Israel Cited By :3 Export Date: 8 December 2020 Correspondence Address: Kintses, B.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research CentreHungary; email: kintses.balint@brc.hu AB - Antimicrobial peptides (AMPs) are key effectors of the innate immune system and promising therapeutic agents. Yet, knowledge on how to design AMPs with minimal cross-resistance to human host-defense peptides remains limited. Here, we systematically assess the resistance determinants ofEscherichia coliagainst 15 different AMPs using chemical-genetics and compare to the cross-resistance spectra of laboratory-evolved AMP-resistant strains. Although generalizations about AMP resistance are common in the literature, we find that AMPs with different physicochemical properties and cellular targets vary considerably in their resistance determinants. As a consequence, cross-resistance is prevalent only between AMPs with similar modes of action. Finally, our screen reveals several genes that shape susceptibility to membrane- and intracellular-targeting AMPs in an antagonistic manner. We anticipate that chemical-genetic approaches could inform future efforts to minimize cross-resistance between therapeutic and human host AMPs. LA - English DB - MTMT ER - TY - JOUR AU - Apjok, Gábor AU - Boross, Gábor AU - Nyerges, Ákos AU - Fekete, Gergely AU - Lázár, Viktória AU - Papp, Balázs AU - Pál, Csaba AU - Csörgő, Bálint TI - Limited evolutionary conservation of the phenotypic effects of antibiotic resistance mutations JF - MOLECULAR BIOLOGY AND EVOLUTION J2 - MOL BIOL EVOL VL - 36 PY - 2019 IS - 8 SP - 1601 EP - 1611 PG - 11 SN - 0737-4038 DO - 10.1093/molbev/msz109 UR - https://m2.mtmt.hu/api/publication/30703953 ID - 30703953 AB - Multidrug-resistant clinical isolates are common in certain pathogens, but rare in others. This pattern may be due to the fact that mutations shaping resistance have species-specific effects. To investigate this issue, we transferred a range of resistance-conferring mutations and a full resistance gene into Escherichia coli and closely related bacteria. We found that resistance mutations in one bacterial species frequently provide no resistance, in fact even yielding drug hypersensitivity in close relatives. In depth analysis of a key gene involved in aminoglycoside resistance (trkH) indicated that preexisting mutations in other genes—intergenic epistasis—underlie such extreme differences in mutational effects between species. Finally, reconstruction of adaptive landscapes under multiple antibiotic stresses revealed that mutations frequently provide multidrug resistance or elevated drug susceptibility (i.e., collateral sensitivity) only with certain combinations of other resistance mutations. We conclude that resistance and collateral sensitivity are contingent upon the genetic makeup of the bacterial population, and such contingency could shape the long-term fate of resistant bacteria. These results underlie the importance of species-specific treatment strategies. LA - English DB - MTMT ER - TY - JOUR AU - Kintses, Bálint AU - Méhi, Orsolya Katinka AU - Ari, Eszter AU - Számel, Mónika AU - Györkei, Ádám AU - Jangir, Pramod Kumar AU - Nagy, István AU - Pál, Ferenc AU - Fekete, Gergely AU - Tengölics, Roland AU - Nyerges, Ákos AU - Likó, István AU - Bálint, Anita AU - Molnár, Tamás AU - Bálint, Balázs AU - Vásárhelyi, Bálint Márk AU - Bustamante, Misshelle AU - Papp, Balázs AU - Pál, Csaba TI - Phylogenetic barriers to horizontal transfer of antimicrobial peptide resistance genes in the human gut microbiota. JF - NATURE MICROBIOLOGY J2 - NAT MICROBIOL VL - 4 PY - 2019 IS - 3 SP - 447 EP - 458 PG - 12 SN - 2058-5276 DO - 10.1038/s41564-018-0313-5 UR - https://m2.mtmt.hu/api/publication/30435652 ID - 30435652 AB - The human gut microbiota has adapted to the presence of antimicrobial peptides (AMPs), which are ancient components of immune defence. Despite its medical importance, it has remained unclear whether AMP resistance genes in the gut microbiome are available for genetic exchange between bacterial species. Here, we show that AMP resistance and antibiotic resistance genes differ in their mobilization patterns and functional compatibilities with new bacterial hosts. First, whereas AMP resistance genes are widespread in the gut microbiome, their rate of horizontal transfer is lower than that of antibiotic resistance genes. Second, gut microbiota culturing and functional metagenomics have revealed that AMP resistance genes originating from phylogenetically distant bacteria have only a limited potential to confer resistance in Escherichia coli, an intrinsically susceptible species. Taken together, functional compatibility with the new bacterial host emerges as a key factor limiting the genetic exchange of AMP resistance genes. Finally, our results suggest that AMPs induce highly specific changes in the composition of the human microbiota, with implications for disease risks. LA - English DB - MTMT ER -