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 - 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 - 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 - THES AU - Spohn, Réka TI - A bakteriális antibiotikum rezisztencia de novo evolúciója és járulékos következményei PB - Szegedi Tudományegyetem (SZTE) PY - 2019 SP - 107 DO - 10.14232/phd.9888 UR - https://m2.mtmt.hu/api/publication/30804304 ID - 30804304 LA - Hungarian 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 - Dunai, Anett AU - Spohn, Réka AU - Farkas, Zoltán AU - Lázár, Viktória AU - Györkei, Ádám AU - Apjok, Gábor AU - Boross, Gábor AU - Szappanos, Balázs AU - Grézal, Gábor AU - Faragó, Anikó AU - Bodai, László AU - Papp, Balázs AU - Pál, Csaba TI - Rapid decline of bacterial drug-resistance in an antibiotic-free environment through phenotypic reversion. JF - ELIFE J2 - ELIFE VL - 8 PY - 2019 PG - 20 SN - 2050-084X DO - 10.7554/eLife.47088 UR - https://m2.mtmt.hu/api/publication/30776198 ID - 30776198 N1 - Funding Agency and Grant Number: H2020 European Research Council [H2020-ERC-2014-CoG 648364]; Gazdasagfejlesztesi es Innovacios Operativ Programm [GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020, GINOP-2.3.2-15-2016-00026]; Hungarian Academy of Sciences Momentum Programme [LP2017-10/2017]; National Research, Development and Innovation Office Elvonal Programme [KKP 126506]; Wellcome Trust [WT 098016/Z/11/Z, WT 084314/Z/07/Z]; National Research, Development and Innovation Office [FK 128775, NKFI-112294]; Magyar Tudomanyos Akademia Lendulet Programme [LP 2012-32/2018]; Magyar Tudomanyos Akademia Postdoctoral Programme [PD-007/2016, PD-038/2015, LP2009-013/2012] Funding text: H2020 European Research Council H2020-ERC-2014-CoG 648364 Resistance Evolution Csaba Pal; Gazdasagfejlesztesi es Innovacios Operativ Programm GINOP-2.3.2-15-2016-00014 Csaba Pal; Gazdasagfejlesztesi es Innovacios Operativ Programm GINOP-2.3.2-15-2016-00020 Csaba Pal; Hungarian Academy of Sciences Momentum Programme LP2017-10/2017 Csaba Pal; National Research, Development and Innovation Office Elvonal Programme KKP 126506 Csaba Pal; Wellcome Trust WT 098016/Z/11/Z Balazs Papp; Gazdasagfejlesztesi es Innovacios Operativ Programm GINOP-2.3.2-15-2016-00026 Balazs Papp; Wellcome Trust WT 084314/Z/07/Z Csaba Pal; National Research, Development and Innovation Office FK 128775 Zoltan Farkas; Magyar Tudomanyos Akademia Lendulet Programme LP 2012-32/2018 Csaba Pal; Magyar Tudomanyos Akademia Postdoctoral Programme PD-007/2016 Viktoria Lazar; Magyar Tudomanyos Akademia Postdoctoral Programme PD-038/2015 Zoltan Farkas; National Research, Development and Innovation Office NKFI-112294 Laszlo Bodai; Magyar Tudomanyos Akademia Lendulet Programme LP2009-013/2012 Balazs Papp; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. AB - Antibiotic resistance typically induces a fitness cost that shapes the fate of antibiotic-resistant bacterial populations. However, the cost of resistance can be mitigated by compensatory mutations elsewhere in the genome, and therefore the loss of resistance may proceed too slowly to be of practical importance. We present our study on the efficacy and phenotypic impact of compensatory evolution in Escherichia coli strains carrying multiple resistance mutations. We have demonstrated that drug-resistance frequently declines within 480 generations during exposure to an antibiotic-free environment. The extent of resistance loss was found to be generally antibiotic-specific, driven by mutations that reduce both resistance level and fitness costs of antibiotic-resistance mutations. We conclude that phenotypic reversion to the antibiotic-sensitive state can be mediated by the acquisition of additional mutations, while maintaining the original resistance mutations. Our study indicates that restricting antimicrobial usage could be a useful policy, but for certain antibiotics only. 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 - GEN AU - Kintses, B AU - Notebaart, RA AU - Szappanos, B AU - Pal, F AU - Gyorkey, A AU - Bogos, B AU - Lazar, V AU - Spohn, Réka AU - Csorgo, B AU - Pal, C AU - Papp, B TI - Forecasting Evolutionary Adaptation by Mapping the Innovative Potential of Underground Metabolism PY - 2015 UR - https://m2.mtmt.hu/api/publication/3085612 ID - 3085612 LA - English DB - MTMT ER - TY - GEN AU - Spohn, Réka AU - Lazar, V AU - Nagy, I AU - Csorgo, B AU - Gyorkei, A AU - Nyerges, A AU - Horvath, B AU - Voros, A AU - Busa-Fekete, R AU - Hrtyan, M AU - Bogos, B AU - Méhi, Orsolya Katinka AU - Fekete, G AU - Szappanos, B AU - Kegl, B AU - Papp, B AU - Pal, C TI - Systems-level analysis of the antibiotic cross-resistance network PY - 2015 UR - https://m2.mtmt.hu/api/publication/3085597 ID - 3085597 LA - English DB - MTMT ER -