@article{MTMT:33632100,
	title = {Plasticity and stereotypic rewiring of the transcriptome upon bacterial evolution of antibiotic resistance},
	url = {https://m2.mtmt.hu/api/publication/33632100},
	author = {Grézal, Gábor and Spohn, Réka and Méhi, Orsolya Katinka and Dunai, Anett and Lázár, Viktória and Bálint, Balázs and Nagy, István and Pál, Csaba and Papp, Balázs},
	doi = {10.1093/molbev/msad020},
	journal-iso = {MOL BIOL EVOL},
	journal = {MOLECULAR BIOLOGY AND EVOLUTION},
	volume = {40},
	unique-id = {33632100},
	issn = {0737-4038},
	abstract = {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.},
	year = {2023},
	eissn = {1537-1719},
	orcid-numbers = {Grézal, Gábor/0000-0003-1685-4791; Méhi, Orsolya Katinka/0009-0004-7918-913X}
}

@article{MTMT:32493048,
	title = {Rationally designed foldameric adjuvants enhance antibiotic efficacy via promoting membrane hyperpolarization},
	url = {https://m2.mtmt.hu/api/publication/32493048},
	author = {Nath Bhaumik, Kaushik and Hetényi, Anasztázia and Olajos, Gábor and Martins, Ana and Spohn, Réka and Németh, Lukács and Jójárt, Balázs and Szili, Petra and Dunai, Anett and Jangir, Pramod Kumar and Daruka, Lejla and Földesi, Imre and Kata, Diána and Pál, Csaba and Martinek, Tamás},
	doi = {10.1039/D1ME00118C},
	journal-iso = {MOL SYST DES ENG},
	journal = {MOLECULAR SYSTEMS DESIGN & ENGINEERING},
	volume = {7},
	unique-id = {32493048},
	issn = {2058-9689},
	abstract = {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.},
	year = {2022},
	eissn = {2058-9689},
	pages = {21-33},
	orcid-numbers = {Hetényi, Anasztázia/0000-0001-8080-6992; Olajos, Gábor/0000-0002-2479-4891; Jangir, Pramod Kumar/0000-0001-8330-0655; Földesi, Imre/0000-0002-3329-8136; Kata, Diána/0000-0002-4432-9380; Martinek, Tamás/0000-0003-3168-8066}
}

@article{MTMT:31038930,
	title = {Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action},
	url = {https://m2.mtmt.hu/api/publication/31038930},
	author = {Kintses, Bálint and Jangir, Pramod Kumar and Fekete, Gergely and Számel, Mónika and Méhi, Orsolya Katinka and Spohn, Réka and Daruka, Lejla and Martins, Ana and Hosseinnia, A. and Gagarinova, A. and Kim, S. and Phanse, S. and Csörgő, Bálint and Györkei, Ádám and Ari, Eszter and Lázár, Viktória and Nagy, István and Babu, M. and Pál, Csaba and Papp, Balázs},
	doi = {10.1038/s41467-019-13618-z},
	journal-iso = {NAT COMMUN},
	journal = {NATURE COMMUNICATIONS},
	volume = {10},
	unique-id = {31038930},
	issn = {2041-1723},
	year = {2019},
	eissn = {2041-1723},
	orcid-numbers = {Jangir, Pramod Kumar/0000-0001-8330-0655; Méhi, Orsolya Katinka/0009-0004-7918-913X; Csörgő, Bálint/0000-0003-0397-6845; Ari, Eszter/0000-0001-7774-1067}
}

@article{MTMT:30865039,
	title = {Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance},
	url = {https://m2.mtmt.hu/api/publication/30865039},
	author = {Spohn, Réka and Daruka, Lejla and Lázár, Viktória and Martins, Ana and Vidovics, Fanni and Grézal, Gábor and Méhi, Orsolya Katinka and Kintses, Bálint and Számel, Mónika and Jangir, Pramod Kumar and Csörgő, Bálint and Györkei, Ádám and Bódi, Zoltán and Faragó, Anikó and Bodai, László and Földesi, Imre and Kata, Diána and Maróti, Gergely and Pap, Bernadett and Wirth, Roland and Papp, Balázs and Pál, Csaba},
	doi = {10.1038/s41467-019-12364-6},
	journal-iso = {NAT COMMUN},
	journal = {NATURE COMMUNICATIONS},
	volume = {10},
	unique-id = {30865039},
	issn = {2041-1723},
	abstract = {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.},
	year = {2019},
	eissn = {2041-1723},
	orcid-numbers = {Grézal, Gábor/0000-0003-1685-4791; Méhi, Orsolya Katinka/0009-0004-7918-913X; Jangir, Pramod Kumar/0000-0001-8330-0655; Csörgő, Bálint/0000-0003-0397-6845; Bodai, László/0000-0001-8411-626X; Földesi, Imre/0000-0002-3329-8136; Kata, Diána/0000-0002-4432-9380; Maróti, Gergely/0000-0002-3705-0461; Wirth, Roland/0000-0002-2383-2323}
}

@mastersthesis{MTMT:30804304,
	title = {A bakteriális antibiotikum rezisztencia de novo evolúciója és járulékos következményei},
	url = {https://m2.mtmt.hu/api/publication/30804304},
	author = {Spohn, Réka},
	doi = {10.14232/phd.9888},
	publisher = {SZTE},
	unique-id = {30804304},
	year = {2019}
}

@article{MTMT:30777054,
	title = {Rapid Evolution of Reduced Susceptibility against a Balanced Dual-Targeting Antibiotic through Stepping-Stone Mutations.},
	url = {https://m2.mtmt.hu/api/publication/30777054},
	author = {Szili, Petra and Draskovits, Gábor and Révész, Tamás and Bogár, Ferenc and Balogh, Dávid and Martinek, Tamás and Daruka, Lejla and Spohn, Réka and Vásárhelyi, Bálint Márk and Czikkely, Márton Simon and Kintses, Bálint and Grézal, Gábor and Ferenc, Györgyi and Pál, Csaba and Nyerges, Ákos},
	doi = {10.1128/AAC.00207-19},
	journal-iso = {ANTIMICROB AGENTS CH},
	journal = {ANTIMICROBIAL AGENTS AND CHEMOTHERAPY},
	volume = {63},
	unique-id = {30777054},
	issn = {0066-4804},
	abstract = {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.},
	keywords = {Antibiotic resistance; genome engineering; gepotidacin},
	year = {2019},
	eissn = {1098-6596},
	orcid-numbers = {Bogár, Ferenc/0000-0002-0611-1452; Martinek, Tamás/0000-0003-3168-8066; Vásárhelyi, Bálint Márk/0000-0003-1782-8691; Grézal, Gábor/0000-0003-1685-4791; Ferenc, Györgyi/0000-0002-3456-319X; Nyerges, Ákos/0000-0002-1581-490X}
}

@article{MTMT:30776198,
	title = {Rapid decline of bacterial drug-resistance in an antibiotic-free environment through phenotypic reversion.},
	url = {https://m2.mtmt.hu/api/publication/30776198},
	author = {Dunai, Anett and Spohn, Réka and Farkas, Zoltán and Lázár, Viktória and Györkei, Ádám and Apjok, Gábor and Boross, Gábor and Szappanos, Balázs and Grézal, Gábor and Faragó, Anikó and Bodai, László and Papp, Balázs and Pál, Csaba},
	doi = {10.7554/eLife.47088},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {8},
	unique-id = {30776198},
	issn = {2050-084X},
	abstract = {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.},
	keywords = {EVOLUTION; Antibiotic resistance; E. coli; evolutionary biology; compensatory mutations},
	year = {2019},
	eissn = {2050-084X},
	orcid-numbers = {Boross, Gábor/0000-0002-7208-5678; Szappanos, Balázs/0000-0002-5075-1799; Grézal, Gábor/0000-0003-1685-4791; Bodai, László/0000-0001-8411-626X}
}

@article{MTMT:3378998,
	title = {Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides},
	url = {https://m2.mtmt.hu/api/publication/3378998},
	author = {Lázár, Viktória and Martins, Ana and Spohn, Réka and Daruka, Lejla and Grézal, Gábor and Fekete, Gergely and Számel, Mónika and Jangir, Pramod Kumar and Kintses, Bálint and Csörgő, Bálint and Nyerges, Ákos and Györkei, Ádám and Kincses, András and Dér, András and Walter, Fruzsina and Deli, Mária Anna and Zsoldiné Urbán, Edit and Hegedüs, Zsófia and Olajos, Gábor and Méhi, Orsolya Katinka and Bálint, Balázs and Nagy, István and Martinek, Tamás and Papp, Balázs and Pál, Csaba},
	doi = {10.1038/s41564-018-0164-0},
	journal-iso = {NAT MICROBIOL},
	journal = {NATURE MICROBIOLOGY},
	volume = {3},
	unique-id = {3378998},
	issn = {2058-5276},
	abstract = {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.},
	year = {2018},
	eissn = {2058-5276},
	pages = {718-731},
	orcid-numbers = {Grézal, Gábor/0000-0003-1685-4791; Jangir, Pramod Kumar/0000-0001-8330-0655; Csörgő, Bálint/0000-0003-0397-6845; Nyerges, Ákos/0000-0002-1581-490X; Walter, Fruzsina/0000-0001-8145-2823; Deli, Mária Anna/0000-0001-6084-6524; Zsoldiné Urbán, Edit/0000-0002-9602-7552; Hegedüs, Zsófia/0000-0002-5546-8167; Olajos, Gábor/0000-0002-2479-4891; Méhi, Orsolya Katinka/0009-0004-7918-913X; Martinek, Tamás/0000-0003-3168-8066}
}

@misc{MTMT:3085612,
	title = {Forecasting Evolutionary Adaptation by Mapping the Innovative Potential of Underground Metabolism},
	url = {https://m2.mtmt.hu/api/publication/3085612},
	author = {Kintses, B and Notebaart, RA and Szappanos, B and Pal, F and Gyorkey, A and Bogos, B and Lazar, V and Spohn, Réka and Csorgo, B and Pal, C and Papp, B},
	unique-id = {3085612},
	year = {2015}
}

@misc{MTMT:3085597,
	title = {Systems-level analysis of the antibiotic cross-resistance network},
	url = {https://m2.mtmt.hu/api/publication/3085597},
	author = {Spohn, Réka and Lazar, V and Nagy, I and Csorgo, B and Gyorkei, A and Nyerges, A and Horvath, B and Voros, A and Busa-Fekete, R and Hrtyan, M and Bogos, B and Méhi, Orsolya Katinka and Fekete, G and Szappanos, B and Kegl, B and Papp, B and Pal, C},
	unique-id = {3085597},
	year = {2015}
}