TY - GEN AU - Daruka, Lejla AU - Márton, Simon Czikkely AU - Petra, Szili AU - Farkas, Zoltán AU - Dávid, Balogh AU - Elvin, Maharramov AU - Thu-Hien, Vu AU - Levente, Sipos AU - Botond, Dávid Vincze AU - Gábor, Grézal AU - Szilvia, Juhász AU - Anett, Dunai AU - Andreea, Daraba AU - Mónika, Számel AU - Tóbiás, Sári AU - Tamás, Stirling AU - Vásárhelyi, Bálint Márk AU - Ari, Eszter AU - Chryso, Christodoulou AU - Máté, Manczinger AU - Márton, Zsolt Enyedi AU - Gábor, Jaksa AU - Stineke, van Houte AU - Elizabeth, Pursey AU - Csaba, Gergő Papp AU - Zóra, Szilovics AU - Lajos, Pintér AU - Lajos, Haracska AU - Attila, Gácser AU - Bálint, Kintses AU - Balázs, Papp AU - Csaba, Pál TI - Antibiotics of the future are prone to resistance in Gram-negative pathogens PY - 2023 UR - https://m2.mtmt.hu/api/publication/34158052 ID - 34158052 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 - 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 - Durcik, M. AU - Nyerges, Ákos AU - Skok, Z AU - Skledar, D.G. AU - Trontelj, J. AU - Zidar, N. AU - Ilaš, J. AU - Zega, A. AU - Cruz, C.D. AU - Tammela, P. AU - Welin, M. AU - Kimbung, Y.R. AU - Focht, D. AU - Benek, O. AU - Révész, Tamás AU - Draskovits, Gábor AU - Szili, Petra AU - Daruka, Lejla AU - Pál, Csaba AU - Kikelj, D. AU - Mašič, L.P. AU - Tomašič, T. TI - New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 213 PY - 2021 PG - 22 SN - 0223-5234 DO - 10.1016/j.ejmech.2021.113200 UR - https://m2.mtmt.hu/api/publication/31855890 ID - 31855890 N1 - University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, H-6726, Hungary Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), Helsinki, 00014, Finland SARomics Biostructures, Medicon Village, Lund, Sweden University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, Hradec Kralove, 500 03, Czech Republic Export Date: 9 February 2021 CODEN: EJMCA Correspondence Address: Mašič, L.P.; University of Ljubljana, Aškerčeva cesta 7, Slovenia; email: Lucija.PeterlinMasic@ffa.uni-lj.si Correspondence Address: Tomašič, T.; University of Ljubljana, Aškerčeva cesta 7, Slovenia; email: Tihomir.Tomasic@ffa.uni-lj.si University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, H-6726, Hungary Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), Helsinki, 00014, Finland SARomics Biostructures, Medicon Village, Lund, Sweden University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, Hradec Kralove, 500 03, Czech Republic Export Date: 22 April 2021 CODEN: EJMCA Correspondence Address: Mašič, L.P.; University of Ljubljana, Aškerčeva cesta 7, Slovenia; email: Lucija.PeterlinMasic@ffa.uni-lj.si Correspondence Address: Tomašič, T.; University of Ljubljana, Aškerčeva cesta 7, Slovenia; email: Tihomir.Tomasic@ffa.uni-lj.si University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, H-6726, Hungary Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), Helsinki, 00014, Finland SARomics Biostructures, Medicon Village, Lund, Sweden University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, Hradec Kralove, 500 03, Czech Republic Export Date: 21 May 2021 CODEN: EJMCA Correspondence Address: Mašič, L.P.; University of Ljubljana, Aškerčeva cesta 7, Slovenia; email: Lucija.PeterlinMasic@ffa.uni-lj.si Correspondence Address: Tomašič, T.; University of Ljubljana, Aškerčeva cesta 7, Slovenia; email: Tihomir.Tomasic@ffa.uni-lj.si AB - The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078–0.0625 μg/mL) and Gram-negative pathogens (MICs: range, 1–2 μg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance. © 2021 Elsevier Masson SAS LA - English DB - MTMT ER - TY - JOUR AU - Nyerges, Ákos AU - Tomasic, Tihomir AU - Durcik, Martina AU - Révész, Tamás AU - Szili, Petra AU - Draskovits, Gábor AU - Bogár, Ferenc AU - Skok, Ziga AU - Zidar, Nace AU - Ilas, Janez AU - Zega, Anamarija AU - Kikelj, Danijel AU - Daruka, Lejla AU - Kintses, Bálint AU - Vásárhelyi, Bálint Márk AU - Földesi, Imre AU - Kata, Diána AU - Welin, Martin AU - Kimbung, Raymond AU - Focht, Dorota AU - Masic, Lucija Peterlin AU - Pál, Csaba TI - Rational design of balanced dual-targeting antibiotics with limited resistance JF - PLOS BIOLOGY J2 - PLOS BIOL VL - 18 PY - 2020 IS - 10 PG - 31 SN - 1544-9173 DO - 10.1371/journal.pbio.3000819 UR - https://m2.mtmt.hu/api/publication/31642956 ID - 31642956 N1 - Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, Department of Medical Chemistry, University of Szeged, Hungary Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary Department of Laboratory Medicine, University of Szeged, Szeged, Hungary SARomics Biostructures, Medicon Village, Lund, Sweden Export Date: 8 December 2020 CODEN: PBLIB Correspondence Address: Mašič, L.P.; University of Ljubljana, Faculty of Pharmacy, Synthetic and Systems Biology Unit, Biological Research CenterSlovenia; email: lucija.peterlin@ffa.uni-lj.si Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, Department of Medical Chemistry, University of Szeged, Hungary Doctoral School of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary HCEMM-BRC Translational Microbiology Lab, Szeged, Hungary Department of Laboratory Medicine, University of Szeged, Szeged, Hungary SARomics Biostructures, Medicon Village, Lund, Sweden Cited By :2 Export Date: 22 April 2021 CODEN: PBLIB Correspondence Address: Mašič, L.P.; University of Ljubljana, Slovenia; email: lucija.peterlin@ffa.uni-lj.si Correspondence Address: Pal, C.; Synthetic and Systems Biology Unit, Hungary; email: cpal@brc.hu AB - Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistantStaphylococcus aureusclinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] <= 1 mu g/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections. 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 - Spohn, Réka AU - Daruka, Lejla AU - Lázár, Viktória AU - Martins, Ana AU - Vidovics, Fanni AU - Grézal, Gábor AU - Méhi, Orsolya Katinka AU - Kintses, Bálint AU - Számel, Mónika AU - Jangir, Pramod Kumar AU - Csörgő, Bálint AU - Györkei, Ádám AU - Bódi, Zoltán AU - Faragó, Anikó AU - Bodai, László AU - Földesi, Imre AU - Kata, Diána AU - Maróti, Gergely AU - Pap, Bernadett AU - Wirth, Roland AU - Papp, Balázs AU - Pál, Csaba TI - Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 10 PY - 2019 PG - 13 SN - 2041-1723 DO - 10.1038/s41467-019-12364-6 UR - https://m2.mtmt.hu/api/publication/30865039 ID - 30865039 N1 - Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, 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 and Molecular Biology, University of Szeged, Szeged, Hungary Department of Laboratory Medicine, University of Szeged, Szeged, Hungary Institute of Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Department of Biotechnology, University of Szeged, Szeged, Hungary Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel University of California, San Francisco, Department of Microbiology and Immunology, San Francisco, CA, United States Cited By :19 Export Date: 24 August 2020 Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research CentreHungary; email: cpal@brc.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, 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 and Molecular Biology, University of Szeged, Szeged, Hungary Department of Laboratory Medicine, University of Szeged, Szeged, Hungary Institute of Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Department of Biotechnology, University of Szeged, Szeged, Hungary Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel University of California, San Francisco, Department of Microbiology and Immunology, San Francisco, CA, United States Cited By :32 Export Date: 14 January 2021 Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research CentreHungary; email: cpal@brc.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, 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 and Molecular Biology, University of Szeged, Szeged, Hungary Department of Laboratory Medicine, University of Szeged, Szeged, Hungary Institute of Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Department of Biotechnology, University of Szeged, Szeged, Hungary Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel University of California, San Francisco, Department of Microbiology and Immunology, San Francisco, CA, United States Cited By :54 Export Date: 30 July 2021 Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Hungary; email: cpal@brc.hu Chemicals/CAS: chloramphenicol, 134-90-7, 2787-09-9, 56-75-7; indolicidin, 140896-21-5; pexiganan, 172820-23-4, 147664-63-9; polymyxin B, 1404-26-8, 1405-20-5; pr 39, 139637-11-9; protamine, 11061-43-1, 9007-31-2, 9012-00-4; tachyplesin, 118231-04-2; Anti-Infective Agents; Antimicrobial Cationic Peptides Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, 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 and Molecular Biology, University of Szeged, Szeged, Hungary Department of Laboratory Medicine, University of Szeged, Szeged, Hungary Institute of Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Department of Biotechnology, University of Szeged, Szeged, Hungary Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel University of California, San Francisco, Department of Microbiology and Immunology, San Francisco, CA, United States Cited By :58 Export Date: 25 August 2021 Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Hungary; email: cpal@brc.hu AB - Antimicrobial peptides (AMPs) are promising antimicrobials, however, the potential of bacterial resistance is a major concern. Here we systematically study the evolution of resistance to 14 chemically diverse AMPs and 12 antibiotics in Escherichia coli. Our work indicates that evolution of resistance against certain AMPs, such as tachyplesin II and cecropin P1, is limited. Resistance level provided by point mutations and gene amplification is very low and antibiotic-resistant bacteria display no cross-resistance to these AMPs. Moreover, genomic fragments derived from a wide range of soil bacteria confer no detectable resistance against these AMPs when introduced into native host bacteria on plasmids. We have found that simple physicochemical features dictate bacterial propensity to evolve resistance against AMPs. Our work could serve as a promising source for the development of new AMP-based therapeutics less prone to resistance, a feature necessary to avoid any possible interference with our innate immune system. LA - English DB - MTMT ER - TY - JOUR AU - Szili, Petra AU - Draskovits, Gábor AU - Révész, Tamás AU - Bogár, Ferenc AU - Balogh, Dávid AU - Martinek, Tamás AU - Daruka, Lejla AU - Spohn, Réka AU - Vásárhelyi, Bálint Márk AU - Czikkely, Márton Simon AU - Kintses, Bálint AU - Grézal, Gábor AU - Ferenc, Györgyi AU - Pál, Csaba AU - Nyerges, Ákos TI - Rapid Evolution of Reduced Susceptibility against a Balanced Dual-Targeting Antibiotic through Stepping-Stone Mutations. JF - ANTIMICROBIAL AGENTS AND CHEMOTHERAPY J2 - ANTIMICROB AGENTS CH VL - 63 PY - 2019 IS - 9 PG - 15 SN - 0066-4804 DO - 10.1128/AAC.00207-19 UR - https://m2.mtmt.hu/api/publication/30777054 ID - 30777054 N1 - Funding Agency and Grant Number: European Research Council [H2020-ERC-2014-CoG 648364]; Wellcome Trust; GINOP (EVOMER); New National Excellence Program of the Ministry of Human Capacities [UNKP-18-3, UNKP-18-4]; "Lendulet" Program of the Hungarian Academy of Sciences; NKFIH [K120220]; Boehringer Ingelheim Fonds; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; Szeged Scientists Academy under Hungarian Ministry of Human Capacities [EMMI: 13725-2/2018/INTFIN]; GINOP (MolMedEx TUMORDNS) [GINOP-2.3.2-15-2016-00020]; [GINOP-2.3.2-15-2016-00014]; [EFOP 3.6.3-VEKOP-16-2017-00009] Funding text: This work was supported by grants from the European Research Council (H2020-ERC-2014-CoG 648364 "Resistance Evolution" to C.P.), the Wellcome Trust (to C.P.), and GINOP (MolMedEx TUMORDNS) GINOP-2.3.2-15-2016-00020, GINOP (EVOMER), GINOP-2.3.2-15-2016-00014 (to C.P.), EFOP 3.6.3-VEKOP-16-2017-00009 (to P.S. and T.R.), and UNKP-18-3 New National Excellence Program of the Ministry of Human Capacities (to P.S.); the "Lendulet" Program of the Hungarian Academy of Sciences (to C.P.), an NKFIH grant K120220 (to B.K.), and a Ph.D. fellowship from the Boehringer Ingelheim Fonds (to A.N.). B.K. was supported by the UNKP-18-4 New National Excellence Program of the Ministry of Human Capacities, the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences, and M. C. was supported by the Szeged Scientists Academy under the sponsorship of the Hungarian Ministry of Human Capacities (EMMI: 13725-2/2018/INTFIN). Összes idézések száma a WoS-ban: 0 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary Department of Medical Chemistry, University of Szeged, Szeged, Hungary Nucleic Acid Synthesis Laboratory, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary Szeged Scientists Academy, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Cited By :2 Export Date: 24 August 2020 CODEN: AMACC Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of SciencesHungary; email: pal.csaba@brc.mta.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary Department of Medical Chemistry, University of Szeged, Szeged, Hungary Nucleic Acid Synthesis Laboratory, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary Szeged Scientists Academy, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Cited By :3 Export Date: 8 December 2020 CODEN: AMACC Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of SciencesHungary; email: pal.csaba@brc.mta.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary Department of Medical Chemistry, University of Szeged, Szeged, Hungary Nucleic Acid Synthesis Laboratory, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary Szeged Scientists Academy, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Cited By :4 Export Date: 5 February 2021 CODEN: AMACC Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Hungary; email: pal.csaba@brc.mta.hu Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary Department of Medical Chemistry, University of Szeged, Szeged, Hungary Nucleic Acid Synthesis Laboratory, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary Szeged Scientists Academy, Szeged, Hungary Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary Cited By :5 Export Date: 25 August 2021 CODEN: AMACC Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Hungary; email: pal.csaba@brc.mta.hu AB - Multitargeting antibiotics, i.e., single compounds capable of inhibiting two or more bacterial targets, are generally considered to be a promising therapeutic strategy against resistance evolution. The rationale for this theory is that multitargeting antibiotics demand the simultaneous acquisition of multiple mutations at their respective target genes to achieve significant resistance. The theory presumes that individual mutations provide little or no benefit to the bacterial host. Here, we propose that such individual stepping-stone mutations can be prevalent in clinical bacterial isolates, as they provide significant resistance to other antimicrobial agents. To test this possibility, we focused on gepotidacin, an antibiotic candidate that selectively inhibits both bacterial DNA gyrase and topoisomerase IV. In a susceptible organism, Klebsiella pneumoniae, a combination of two specific mutations in these target proteins provide an >2,000-fold reduction in susceptibility, while individually, none of these mutations affect resistance significantly. Alarmingly, strains with decreased susceptibility against gepotidacin are found to be as virulent as the wild-type Klebsiella pneumoniae strain in a murine model. Moreover, numerous pathogenic isolates carry mutations which could promote the evolution of clinically significant reduction of susceptibility against gepotidacin in the future. As might be expected, prolonged exposure to ciprofloxacin, a clinically widely employed gyrase inhibitor, coselected for reduced susceptibility against gepotidacin. We conclude that extensive antibiotic usage could select for mutations that serve as stepping-stones toward resistance against antimicrobial compounds still under development. Our research indicates that even balanced multitargeting antibiotics are prone to resistance evolution. LA - English DB - MTMT ER - TY - JOUR AU - Szabó, Renáta AU - Ménesi, Rudolf AU - Molnár, Andor AU - Szalai, Zita AU - Daruka, Lejla AU - Tóth, Gábor AU - Gardi, János AU - Gálfi, Márta AU - Börzsei, Denise AU - Kupai, Krisztina AU - Juhász, Anna AU - Radács, Marianna AU - László, Ferenc AU - Varga, Csaba AU - Pósa, Anikó TI - New Metabolic Influencer on Oxytocin Release: The Ghrelin JF - MOLECULES J2 - MOLECULES VL - 24 PY - 2019 IS - 4 PG - 8 SN - 1420-3049 DO - 10.3390/molecules24040735 UR - https://m2.mtmt.hu/api/publication/30446615 ID - 30446615 N1 - The study was supported by GINOP-2.3.2-15-2016-00062 and the Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT is acknowledged. Furthermore, this work has been supported by the European Union, cofinanced by the European Social Fund EFOP-3.6.2-16-2017-00009. LA - English DB - MTMT ER - TY - JOUR AU - Bocsik, Alexandra AU - Gróf, Ilona AU - Kiss, Lóránd AU - Ötvös, Ferenc AU - Zsíros, Ottó AU - Daruka, Lejla AU - Fülöp, Lívia AU - Vastag, Monika AU - Kittel, Ágnes AU - Imre, Norbert AU - Martinek, Tamás AU - Pál, Csaba AU - Révész, Piroska AU - Deli, Mária Anna TI - Dual Action of the PN159/KLAL/MAP Peptide. Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability. TS - Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability. JF - PHARMACEUTICS J2 - PHARMACEUTICS VL - 11 PY - 2019 IS - 2 PG - 21 SN - 1999-4923 DO - 10.3390/pharmaceutics11020073 UR - https://m2.mtmt.hu/api/publication/30434125 ID - 30434125 AB - The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood⁻brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects. LA - English DB - MTMT ER -