TY - GEN 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 PY - 2024 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 - 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 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 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 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 - TY - JOUR AU - Lázár, Viktória AU - Martins, Ana AU - Spohn, Réka AU - Daruka, Lejla AU - Grézal, Gábor AU - Fekete, Gergely AU - Számel, Mónika AU - Jangir, Pramod Kumar AU - Kintses, Bálint AU - Csörgő, Bálint AU - Nyerges, Ákos AU - Györkei, Ádám AU - Kincses, András AU - Dér, András AU - Walter, Fruzsina AU - Deli, Mária Anna AU - Zsoldiné Urbán, Edit AU - Hegedüs, Zsófia AU - Olajos, Gábor AU - Méhi, Orsolya Katinka AU - Bálint, Balázs AU - Nagy, István AU - Martinek, Tamás AU - Papp, Balázs AU - Pál, Csaba TI - Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides JF - NATURE MICROBIOLOGY J2 - NAT MICROBIOL VL - 3 PY - 2018 IS - 6 SP - 718 EP - 731 PG - 14 SN - 2058-5276 DO - 10.1038/s41564-018-0164-0 UR - https://m2.mtmt.hu/api/publication/3378998 ID - 3378998 N1 - Megosztott első szerzőség. These authors contributed equally to this work: Viktória Lázár and Ana Martins. AB - Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections. LA - English DB - MTMT ER - TY - JOUR AU - Natan, E AU - Endoh, T AU - Haim-Vilmovsky, L AU - Flock, T AU - Chalancon, G AU - Hopper, JTS AU - Kintses, Bálint AU - Horváth, Péter AU - Daruka, Lejla AU - Fekete, Gergely AU - Pál, Csaba AU - Papp, Balázs AU - Őszi, Erika AU - Magyar, Zoltán AU - Marsh, JA AU - Elcock, AH AU - Babu, MM AU - Robinson, CV AU - Sugimoto, N AU - Teichmann, SA TI - Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins JF - NATURE STRUCTURAL & MOLECULAR BIOLOGY J2 - NAT STRUCT MOL BIOL VL - 25 PY - 2018 IS - 3 SP - 279 EP - 288 PG - 10 SN - 1545-9993 DO - 10.1038/s41594-018-0029-5 UR - https://m2.mtmt.hu/api/publication/3338278 ID - 3338278 AB - Cotranslational protein folding can facilitate rapid formation of functional structures. However, it can also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched toward the C termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur before assembly. Using high-throughput imaging of protein homomers in Escherichia coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization. LA - English DB - MTMT ER -