TY - JOUR AU - Pál, Csaba AU - Papp, Balázs TI - How selection shapes the short- and long-term dynamics of molecular evolution JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 120 PY - 2023 IS - 33 PG - 3 SN - 0027-8424 DO - 10.1073/pnas.2311012120 UR - https://m2.mtmt.hu/api/publication/34106372 ID - 34106372 N1 - Synthetic and System Biology Unit, Biological Research Centre, National Laboratory of Biotechnology, Eötvös Loránd Research Network, Szeged, HU-6726, Hungary Hungarian Centre of Excellence for Molecular Medicine, Biological Research Centre Metabolic Systems Biology Research Group, Szeged, HU-6726, Hungary National Laboratory for Health Security, Biological Research Centre, Eötvös Loránd Research Network, Szeged, HU-6726, Hungary Export Date: 22 January 2024 CODEN: PNASA Correspondence Address: Pála, C.; Synthetic and System Biology Unit, Hungary; email: cpal@brc.hu LA - English DB - MTMT ER - TY - JOUR AU - Sterle, Masa AU - Durcik, Martina AU - Stevenson, Clare E. M. AU - Henderson, Sara R. AU - Szili, Petra AU - Czikkely, Márton Simon AU - Lawson, David M. AU - Maxwell, Anthony AU - Cahard, Dominique AU - Kikelj, Danijel AU - Zidar, Nace AU - Pál, Csaba AU - Masic, Lucija Peterlin AU - Ilas, Janez AU - Tomasic, Tihomir AU - Cotman, Andrej Emanuel AU - Zega, Anamarija TI - Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens JF - ACS OMEGA J2 - ACS OMEGA VL - 8 PY - 2023 SP - 24387 EP - 24395 PG - 9 SN - 2470-1343 DO - 10.1021/acsomega.3c01930 UR - https://m2.mtmt.hu/api/publication/34067433 ID - 34067433 N1 - Funding Agency and Grant Number: Slovenian Research Agency (ARRS) [P1-0208]; ARRS [JI-3031, BI-FR/22-23-PROTEUS-004]; BBSRC Institute Strategic Programme Grant [BB/P012523/1]; Innovative Medicines Initiative Joint Undertaking from the European Union [115583]; EFPIA companies' Funding text: This work was supported by the Slovenian Research Agency (ARRS) core funding P1-0208, ARRS grant JI-3031, and bilateral grant BI-FR/22-23-PROTEUS-004. Work in A.M.'s lab was supported by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I03 under proposal MX18565. Maja Frelih is acknowledged for acquisition of HRMS spectra. X-ray crystallography presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, whose resources comprised financial contributions from the European Union's seventh framework program (FP7/2007-2013) and EFPIA companies' in-kind contribution. AB - We present a new series of 2-aminobenzothiazole-basedDNA gyraseB inhibitors with promising activity against ESKAPE bacterial pathogens.Based on the binding information extracted from the cocrystal structureof DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemicalspace of the benzothiazole-based series to the C5 position of thebenzothiazole ring. In particular, compound E showedlow nanomolar inhibition of DNA gyrase (IC50 < 10 nM)and broad-spectrum antibacterial activity against pathogens belongingto the ESKAPE group, with the minimum inhibitory concentration <0.03 & mu;g/mL for most Gram-positive strains and 4-16 & mu;g/mLagainst Gram-negative E. coli, Acinetobacter baumannii, Pseudomonasaeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, acombination of docking calculations, molecular dynamics (MD) simulations,and MD-derived structure-based pharmacophore modeling was performed.The computational analysis has revealed that the substitution at positionC5 can be used to modify the physicochemical properties and antibacterialspectrum and enhance the inhibitory potency of the compounds. Additionally,a discussion of challenges associated with the synthesis of 5-substituted2-aminobenzothiazoles is presented. LA - English DB - MTMT ER - TY - JOUR AU - Jangir, Pramod Kumar AU - Ogunlana, Lois AU - Szili, Petra AU - Czikkely, Márton Simon AU - Shaw, Liam P AU - Stevens, Emily J AU - Yang, Yu AU - Yang, Qiue AU - Wang, Yang AU - Pál, Csaba AU - Walsh, Timothy R AU - MacLean, Craig R TI - The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence JF - ELIFE J2 - ELIFE VL - 12 PY - 2023 PG - 22 SN - 2050-084X DO - 10.7554/eLife.84395 UR - https://m2.mtmt.hu/api/publication/33773756 ID - 33773756 N1 - Funding Agency and Grant Number: Wellcome Trust [106918/Z/15Z]; Medical Research Council [MR/S013768/1]; National Natural Science Foundation of China [81861138051]; European Research Council [GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020]; Hungarian Academy of Sciences Momentum [BB/M011224/1]; National Research, Development and Innovation Office [UNKP-21-4-New]; National Laboratories Program, National Laboratory of Biotechnology Grant [H2020-ERC-2019-PoC 862077]; National Research, Development and Innovation Office, Hungary; Biotechnology and Biological Sciences Research Council [LP -2017-10/2017]; Gazdasagfejlesztesi es Innovacios Operativ Program; Biotechnology and Biological Sciences Research Council; Ministry for Innovation and Technology Funding text: Wellcome Trust 106918/Z/15Z Craig R MacLeanMedical Research Council MR/S013768/1 Craig R MacLean Timothy R WalshNational Natural Science Foundation of China 81861138051 Yang WangEuropean Research Council H2020-ERC-2014-CoG 648364 -Resistance Evolution Csaba PalEuropean Research Council H2020-ERC-2019-PoC 862077-Aware Csaba PalHungarian Academy of Sciences Momentum 'Celzott Lenduelet' Programme LP -2017-10/2017 Csaba Pal National Research, Development and Innovation Office Elvonal' Programme KKP 126506 Csaba PalNational Laboratories Program, National Laboratory of Biotechnology Grant NKFIH-871-3/2020 Csaba Pal Gazdasagfejlesztesi es Innovacios Operativ Program GINOP-2.3.2-15-2016-00014 Csaba PalGazdasagfejlesztesi es Innovacios Operativ Program GINOP-2.3.2-15-2016-00020 (MolMedEx TUMORDNS Csaba PalBiotechnology and Biological Sciences Research Council BB/M011224/1 Liam P ShawMinistry for Innovation and Technology UNKP-21-4-New Petra Szili Ministry for Innovation and Technology FEIF/433-4/2020-ITM_ SZERZ Marton CzikkelyThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. AB - Antimicrobial peptides (AMPs) offer a promising solution to the antibiotic resistance crisis. However, an unresolved serious concern is that the evolution of resistance to therapeutic AMPs may generate cross-resistance to host AMPs, compromising a cornerstone of the innate immune response. We systematically tested this hypothesis using globally disseminated mobile colistin resistance (MCR) that has been selected by the use of colistin in agriculture and medicine. Here, we show that MCR provides a selective advantage to Escherichia coli in the presence of key AMPs from humans and agricultural animals by increasing AMP resistance. Moreover, MCR promotes bacterial growth in human serum and increases virulence in a Galleria mellonella infection model. Our study shows how the anthropogenic use of AMPs can drive the accidental evolution of resistance to the innate immune system of humans and animals. These findings have major implications for the design and use of therapeutic AMPs and suggest that MCR may be difficult to eradicate, even if colistin use is withdrawn. LA - English DB - MTMT ER - TY - JOUR AU - Durcik, Martina AU - Cotman, Andrej Emanuel AU - Toplak, Žan AU - Možina, Štefan AU - Skok, Žiga AU - Szili, Petra AU - Czikkely, Márton Simon AU - Maharramov, Elvin AU - Vu, Thu Hien AU - Piras, Maria Vittoria AU - Zidar, Nace AU - Ilaš, Janez AU - Zega, Anamarija AU - Trontelj, Jurij AU - Pardo, Luis A. AU - Hughes, Diarmaid AU - Huseby, Douglas AU - Berruga-Fernández, Tália AU - Cao, Sha AU - Simoff, Ivailo AU - Svensson, Richard AU - Korol, Sergiy V. AU - Jin, Zhe AU - Vicente, Francisca AU - Ramos, Maria C. AU - Mundy, Julia E. A. AU - Maxwell, Anthony AU - Stevenson, Clare E. M. AU - Lawson, David M. AU - Glinghammar, Björn AU - Sjöström, Eva AU - Bohlin, Martin AU - Oreskär, Joanna AU - Alvér, Sofie AU - Janssen, Guido V. AU - Sterk, Geert Jan AU - Kikelj, Danijel AU - Pál, Csaba AU - Tomašič, Tihomir AU - Peterlin Mašič, Lucija TI - New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM VL - 66 PY - 2023 IS - 6 SP - 3968 EP - 3994 PG - 27 SN - 0022-2623 DO - 10.1021/acs.jmedchem.2c01905 UR - https://m2.mtmt.hu/api/publication/33714284 ID - 33714284 N1 - Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, H-6726, Hungary Max Planck Institute for Multidisciplinary Sciences, Oncophysiology, Hermann-Rein-Str. 3, Göttingen, 37075, Germany Department of Medical Biochemistry and Microbiology, Uppsala University, Husargatan 3, Uppsala, 75123, Sweden Drug Optimization and Pharmaceutical Profiling Platform (UDOPP) Department of Pharmacy, Uppsala University, Husargatan 3, Uppsala, 75123, Sweden Department of Medical Cell Biology, Uppsala University, Husargatan 3, Uppsala, 75123, Sweden Fundación Medina, Avenida del Conocimiento 34, Parque Tecnológico Ciencias de la Salud, Granada, 18016, Spain Department of Biochemistry and Metabolism, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, United Kingdom Department of Chemical and Pharmaceutical Toxicology, RISE Research Institutes of Sweden, Södertälje, 15136, Sweden Department of Chemical Processes and Pharmaceutical Development, RISE Research Institutes of Sweden, Södertälje, 15136, Sweden Medicinal Chemistry Division, Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam, 1081 HZ, Netherlands Export Date: 27 March 2023 CODEN: JMCMA Correspondence Address: Tomašič, T.; Faculty of Pharmacy, Aškerčeva cesta 7, Slovenia; email: Tihomir.Tomasic@ffa.uni-lj.si Correspondence Address: Peterlin Mašič, L.; Faculty of Pharmacy, Aškerčeva cesta 7, Slovenia; email: Lucija.PeterlinMasic@ffa.uni-lj.si 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 - Grézal, Gábor AU - Spohn, Réka AU - Méhi, Orsolya Katinka AU - Dunai, Anett AU - Lázár, Viktória AU - Bálint, Balázs AU - Nagy, István AU - Pál, Csaba AU - Papp, Balázs TI - Plasticity and stereotypic rewiring of the transcriptome upon bacterial evolution of antibiotic resistance JF - MOLECULAR BIOLOGY AND EVOLUTION J2 - MOL BIOL EVOL VL - 40 PY - 2023 IS - 2 SN - 0737-4038 DO - 10.1093/molbev/msad020 UR - https://m2.mtmt.hu/api/publication/33632100 ID - 33632100 N1 - Funding Agency and Grant Number: Lendulet program of the Hungarian Academy of Sciences [LP-2009-013/2012, LP-2012-32/2018]; ELKH Lenduelet program [LP-2017-2010/2020]; Wellcome Trust WT [098016/Z/11/Z]; European Research Council [648364, 862077]; National Research, Development and Innovation Office; Ministry for Innovation and Technology [KKP KH125616, 126506, RRF-2.3.1-21-2022-00006, GINOP-2.3.2-15-2016-00026, GINOP-2.3.2-15-2 016-00014, GINOP-2.3.2-15-2 016-00020]; National Laboratory of Biotechnology Grant [2022-2.1.1-NL-2022-00008]; European Union [739593]; NKFIH [FK124254]; Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences [BO/608/21] Funding text: This work was supported by the "Lendulet" program of the Hungarian Academy of Sciences LP-2009-013/2012 (B.P.), LP-2012-32/2018 (C.P.), the ELKH Lenduelet program LP-2017-2010/2020 (C.P.), the Wellcome Trust WT 098016/Z/11/Z (B.P.), The European Research Council H2020-ERC-2014-CoG 648364-Resistance Evolution (C.P.), and H2020-ERC-2019-PoC 862077-Aware (C.P.), the National Research, Development and Innovation Office and the Ministry for Innovation and Technology under the "Frontline" program KKP KH125616 and 126506 (B.P. and C.P.), RRF-2.3.1-21-2022-00006 (B.P.), GINOP-2.3.2-15-2016-00026 (iChamber, B.P.), GINOP-2.3.2-15-2 016-00014 (EVOMER, C.P. and B.P.), GINOP-2.3.2-15-2 016-00020 (MolMedEx TUMORDNS, C.P.), National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P. and B.P.), The European Union's Horizon 202 0 research and innovation program under grant agreement No 739593 (B.P.). NKFIH grant FK124254 (O.M.), the Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences BO/608/21 (R.S.). AB - Bacterial evolution of antibiotic resistance frequently has deleterious side effects on microbial growth, virulence, and susceptibility to other antimicrobial agents. However, it is unclear how these trade-offs could be utilized for manipulating antibiotic resistance in the clinic, not least because the underlying molecular mechanisms are poorly understood. Using laboratory evolution, we demonstrate that clinically relevant resistance mutations in Escherichia coli constitutively rewire a large fraction of the transcriptome in a repeatable and stereotypic manner. Strikingly, lineages adapted to functionally distinct antibiotics and having no resistance mutations in common show a wide range of parallel gene expression changes that alter oxidative stress response, iron homeostasis, and the composition of the bacterial outer membrane and cell surface. These common physiological alterations are associated with changes in cell morphology and enhanced sensitivity to antimicrobial peptides. Finally, the constitutive transcriptomic changes induced by resistance mutations are largely distinct from those induced by antibiotic stresses in the wild-type. This indicates a limited role for genetic assimilation of the induced antibiotic stress response during resistance evolution. Our work suggests that diverse resistance mutations converge on similar global transcriptomic states that shape genetic susceptibility to antimicrobial compounds. 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 - Nath Bhaumik, Kaushik AU - Hetényi, Anasztázia AU - Olajos, Gábor AU - Martins, Ana AU - Spohn, Réka AU - Németh, Lukács AU - Jójárt, Balázs AU - Szili, Petra AU - Dunai, Anett AU - Jangir, Pramod Kumar AU - Daruka, Lejla AU - Földesi, Imre AU - Kata, Diána AU - Pál, Csaba AU - Martinek, Tamás TI - Rationally designed foldameric adjuvants enhance antibiotic efficacy via promoting membrane hyperpolarization JF - MOLECULAR SYSTEMS DESIGN & ENGINEERING J2 - MOL SYST DES ENG VL - 7 PY - 2022 IS - 1 SP - 21 EP - 33 PG - 13 SN - 2058-9689 DO - 10.1039/D1ME00118C UR - https://m2.mtmt.hu/api/publication/32493048 ID - 32493048 N1 - Funding Agency and Grant Number: European Research CouncilEuropean Research Council (ERC)European Commission [H2020-ERC-2014-CoG 648364, H2020-ERC-2019-PoC 862077]; ELKH Lendulet Programme [LP-2017-10/2020]; National Research, Development and Innovation Office, HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [KKP 126506]; National Laboratory of Biotechnology Grant [NKFIH-871-3/2020, GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020]; NKFINational Research, Development & Innovation Office (NRDIO) - Hungary [PD 116222, K134754]; Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT] Funding text: The study was supported by the following research grants: European Research Council H2020-ERC-2014-CoG 648364-Resistance Evolution (CP); European Research Council H2020-ERC-2019-PoC 862077-Aware (CP), ELKH Lendulet Programme LP-2017-10/2020 (CP); 'Elvonal' Programme KKP 126506 of the National Research, Development and Innovation Office, Hungary (CP), National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (CP), GINOP-2.3.2-15-2016-00014 (EVOMER) (CP, TAM), GINOP-2.3.2-15-2016-00020 (MolMedEx TUMORDNS) (CP), and NKFI PD 116222 (AM), NKFI K134754 (TAM), Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT (TAM). The authors thank Dora Bokor, PharmD, for proofreading the manuscript. AB - The negative membrane potential of bacterial cells influences crucial cellular processes. Inspired by the molecular scaffold of the antimicrobial peptide PGLa, we have developed antimicrobial foldamers with a computer-guided design strategy. The novel PGLa analogues induce sustained membrane hyperpolarization. When co-administered as an adjuvant, the resulting compounds - PGLb1 and PGLb2 - have substantially reduced the level of antibiotic resistance of multi-drug resistant Escherichia coli, Klebsiella pneumoniae and Shigella flexneri clinical isolates. The observed antibiotic potentiation was mediated by hyperpolarization of the bacterial membrane caused by the alteration of cellular ion transport. Specifically, PGLb1 and PGLb2 are selective ionophores that enhance the Goldman-Hodgkin-Katz potential across the bacterial membrane. These findings indicate that manipulating bacterial membrane electrophysiology could be a valuable tool to overcome antimicrobial resistance. LA - English DB - MTMT ER - TY - JOUR AU - Manczinger, Máté AU - Koncz, Balázs AU - Balogh, Gergő Mihály AU - Papp, Benjamin Tamás AU - Asztalos, Leo AU - Kemény, Lajos AU - Papp, Balázs AU - Pál, Csaba TI - Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity JF - NATURE CANCER J2 - NAT CANCER VL - 2 PY - 2021 IS - 9 SP - 950 EP - 961 PG - 26 SN - 2662-1347 DO - 10.1038/s43018-021-00226-4 UR - https://m2.mtmt.hu/api/publication/32113397 ID - 32113397 N1 - Funding Agency and Grant Number: European Research CouncilEuropean Research Council (ERC)European Commission [648364]; Hungarian Academy of SciencesHungarian Academy of Sciences [LP-2017-10/2017]; National Research, Development and Innovation Office, HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [KKP-126506]; EVOMER [GINOP-2.3.2-15-2016-00014]; MolMedEx TUMORDNS [GINOP-2.3.2-15-2016-00020, GINOP-2.3.3-15-2016-00001, GINOP-2.3.2-15-2016-00026]; 'Frontline' Research Excellence Program of the National Research, Development and Innovation Office, Hungary [KKP-129814]; European UnionEuropean Commission [739593]; New National Excellence Program of the Ministry of Human Capacities [UNKP-20-5]; Bolyai Janos Research Fellowship of the Hungarian Academy of SciencesHungarian Academy of Sciences; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-20-2, UNKP-19-3, UNKP-20-4, UNKP-20-3]; Szeged Scientists Academy under the sponsorship of the Hungarian Ministry of Innovation and Technology [FEIF/433-4/2020-ITM_SZERZ] Funding text: We thank T. Lenz for earlier discussions on this topic and for providing us with the raw data on HED values of HLA-I allele pairs. We also thank the anonymous reviewers for their insightful suggestions on the manuscript, and B. Gyorffy. for his suggestions on survival analysis. The results here are in part based on data generated by the TCGA Research Network (https://www.cancer.gov/tcga).We thank H. Ye for providing the HLA genotype data of TCGA patients. Similarly, we thank R. Marty, J. Font-Burgada and H. Carter for sending HLA genotype data of TCGA patients for earlier analyses. The study was supported by the following research grants: The European Research Council (H2020-ERC-2014-CoG, no. 648364 -Resistance Evolution, to C.P.); `Celzott Lendulet' Program of the Hungarian Academy of Sciences (LP-2017-10/2017, to C.P.); `Frontline' Research Excellence Program of the National Research, Development and Innovation Office, Hungary (KKP-126506, to C.P.); EVOMER (GINOP-2.3.2-15-2016-00014, to C.P. and B.P.); MolMedEx TUMORDNS (GINOP-2.3.2-15-2016-00020 and GINOP-2.3.3-15-2016-00001, to C.P., and GINOP-2.3.2-15-2016-00026, to B.P.); and 'Frontline' Research Excellence Program of the National Research, Development and Innovation Office, Hungary (KKP-129814, to B.P.). The project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 739593 (to B.P., L.K. and M.M). M.M. was supported by the New National Excellence Program of the Ministry of Human Capacities (UNKP-20-5) and by the Bolyai Janos Research Fellowship of the Hungarian Academy of Sciences. L.A. was supported by the New National Excellence Program of the Ministry for Innovation and Technology (UNKP-20-2). G.M.B. was supported by the New National Excellence Program of the Ministry for Innovation and Technology (UNKP-19-3). B.K. was supported by the New National Excellence Program of the Ministry for Innovation and Technology (UNKP-20-4). B.T.P. was supported by the New National Excellence Program of the Ministry for Innovation and Technology (UNKP-20-3). This research work was conducted with the support of the Szeged Scientists Academy under the sponsorship of the Hungarian Ministry of Innovation and Technology (FEIF/433-4/2020-ITM_SZERZ). We thank D. Bokor for proofreading of the manuscript. Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, Eötvös Loránd Research Network (ELKH), Szeged, Hungary Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary MTA-SZTE Dermatological Research Group, Eötvös Loránd Research Network (ELKH), University of Szeged, Szeged, Hungary HCEMM-USZ Skin Research Group, Szeged, Hungary Szeged Scientist Academy, Szeged, Hungary HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary Export Date: 23 September 2021 Correspondence Address: Manczinger, M.; Biological Research Centre, Hungary; email: manczinger.mate@brc.hu Correspondence Address: Pál, C.; Biological Research Centre, Hungary; email: cpal@brc.hu AB - Human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response are unknown. Here we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles and found that patients with cancer who were carrying HLA-I alleles with high peptide-binding promiscuity have significantly worse prognosis after immune checkpoint inhibition. This can be explained by a reduced capacity of the immune system to discriminate tumor neopeptides from self-peptides when patients carry highly promiscuous HLA-I variants, shifting the regulation of tumor-infiltrating T cells from activation to tolerance. In summary, HLA-I peptide-binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner, and could underlie a negative trade-off between antitumor immunity and genetic susceptibility to viral infections. Manczinger and colleagues define 'promiscuity' as a feature of HLA-I alleles representing peptide repertoire breadth; promiscuous alleles may promote a more tolerant tumor microenvironment and negatively impact tumor immune surveillance. LA - English DB - MTMT ER -