@article{MTMT:34106372, title = {How selection shapes the short- and long-term dynamics of molecular evolution}, url = {https://m2.mtmt.hu/api/publication/34106372}, author = {Pál, Csaba and Papp, Balázs}, doi = {10.1073/pnas.2311012120}, journal-iso = {P NATL ACAD SCI USA}, journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, volume = {120}, unique-id = {34106372}, issn = {0027-8424}, year = {2023}, eissn = {1091-6490} } @article{MTMT:34067433, title = {Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens}, url = {https://m2.mtmt.hu/api/publication/34067433}, author = {Sterle, Masa and Durcik, Martina and Stevenson, Clare E. M. and Henderson, Sara R. and Szili, Petra and Czikkely, Márton Simon and Lawson, David M. and Maxwell, Anthony and Cahard, Dominique and Kikelj, Danijel and Zidar, Nace and Pál, Csaba and Masic, Lucija Peterlin and Ilas, Janez and Tomasic, Tihomir and Cotman, Andrej Emanuel and Zega, Anamarija}, doi = {10.1021/acsomega.3c01930}, journal-iso = {ACS OMEGA}, journal = {ACS OMEGA}, volume = {8}, unique-id = {34067433}, issn = {2470-1343}, abstract = {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.}, year = {2023}, eissn = {2470-1343}, pages = {24387-24395}, orcid-numbers = {Henderson, Sara R./0000-0003-2078-639X; Maxwell, Anthony/0000-0002-5756-6430} } @article{MTMT:33773756, title = {The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence}, url = {https://m2.mtmt.hu/api/publication/33773756}, author = {Jangir, Pramod Kumar and Ogunlana, Lois and Szili, Petra and Czikkely, Márton Simon and Shaw, Liam P and Stevens, Emily J and Yang, Yu and Yang, Qiue and Wang, Yang and Pál, Csaba and Walsh, Timothy R and MacLean, Craig R}, doi = {10.7554/eLife.84395}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {12}, unique-id = {33773756}, issn = {2050-084X}, abstract = {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.}, year = {2023}, eissn = {2050-084X}, orcid-numbers = {Jangir, Pramod Kumar/0000-0001-8330-0655} } @article{MTMT:33714284, title = {New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus}, url = {https://m2.mtmt.hu/api/publication/33714284}, author = {Durcik, Martina and Cotman, Andrej Emanuel and Toplak, Žan and Možina, Štefan and Skok, Žiga and Szili, Petra and Czikkely, Márton Simon and Maharramov, Elvin and Vu, Thu Hien and Piras, Maria Vittoria and Zidar, Nace and Ilaš, Janez and Zega, Anamarija and Trontelj, Jurij and Pardo, Luis A. and Hughes, Diarmaid and Huseby, Douglas and Berruga-Fernández, Tália and Cao, Sha and Simoff, Ivailo and Svensson, Richard and Korol, Sergiy V. and Jin, Zhe and Vicente, Francisca and Ramos, Maria C. and Mundy, Julia E. A. and Maxwell, Anthony and Stevenson, Clare E. M. and Lawson, David M. and Glinghammar, Björn and Sjöström, Eva and Bohlin, Martin and Oreskär, Joanna and Alvér, Sofie and Janssen, Guido V. and Sterk, Geert Jan and Kikelj, Danijel and Pál, Csaba and Tomašič, Tihomir and Peterlin Mašič, Lucija}, doi = {10.1021/acs.jmedchem.2c01905}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, volume = {66}, unique-id = {33714284}, issn = {0022-2623}, year = {2023}, eissn = {1520-4804}, pages = {3968-3994}, orcid-numbers = {Durcik, Martina/0000-0002-9218-1771; Cotman, Andrej Emanuel/0000-0003-2528-396X; Možina, Štefan/0000-0002-7416-6981; Piras, Maria Vittoria/0000-0002-0663-3373; Zidar, Nace/0000-0003-1905-0158; Ilaš, Janez/0000-0002-0124-0474; Zega, Anamarija/0000-0003-4065-0019; Pardo, Luis A./0000-0003-1375-4349; Huseby, Douglas/0000-0001-9974-578X; Berruga-Fernández, Tália/0000-0001-6459-1397; Simoff, Ivailo/0000-0001-6522-7191; Korol, Sergiy V./0000-0001-8279-2790; Ramos, Maria C./0000-0002-3674-615X; Maxwell, Anthony/0000-0002-5756-6430; Tomašič, Tihomir/0000-0001-5534-209X; Peterlin Mašič, Lucija/0000-0003-0624-8472} } @article{MTMT:33634821, title = {Characterization of antibiotic resistomes by reprogrammed bacteriophage-enabled functional metagenomics in clinical strains}, url = {https://m2.mtmt.hu/api/publication/33634821}, author = {Apjok, Gábor and Számel, Mónika and Christodoulou, Chryso and Seregi, Viktória and Vásárhelyi, Bálint Márk and Stirling, Tamás and Eszenyi, Bálint Dénes and Sári , Tóbiás and Vidovics, Fanni and Nagrand, Erika and Kovács, Dorina and Szili, Petra and Lantos, Ildikó Ilona and Méhi, Orsolya Katinka and Jangir, Pramod Kumar and Herczeg, Róbert and Gálik, Bence and Urbán, Péter and Gyenesei, Attila and Draskovits, Gábor and Nyerges, Ákos and Fekete, Gergely and Bodai, László and Zsindely, Nóra and Dénes, Béla and Yosef, Ido and Qimron, Udi and Papp, Balázs and Pál, Csaba and Kintses, Bálint}, doi = {10.1038/s41564-023-01320-2}, journal-iso = {NAT MICROBIOL}, journal = {NATURE MICROBIOLOGY}, volume = {8}, unique-id = {33634821}, issn = {2058-5276}, abstract = {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.}, year = {2023}, eissn = {2058-5276}, pages = {410-423}, orcid-numbers = {Apjok, Gábor/0000-0002-8627-2378; Vásárhelyi, Bálint Márk/0000-0003-1782-8691; Stirling, Tamás/0000-0002-8964-6443; Méhi, Orsolya Katinka/0009-0004-7918-913X; Jangir, Pramod Kumar/0000-0001-8330-0655; Herczeg, Róbert/0000-0002-5903-0082; Gálik, Bence/0000-0002-3949-7005; Nyerges, Ákos/0000-0002-1581-490X; Bodai, László/0000-0001-8411-626X; Zsindely, Nóra/0000-0002-6189-3100; Dénes, Béla/0000-0002-9889-529X} } @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:32813213, title = {Proteome-wide landscape of solubility limits in a bacterial cell}, url = {https://m2.mtmt.hu/api/publication/32813213}, author = {Györkei, Ádám and Daruka, Lejla and Balogh, Dávid and Őszi, Erika and Magyar, Zoltán and Szappanos, Balázs and Fekete, Gergely and Fuxreiter, Mónika and Horváth, Péter and Pál, Csaba and Kintses, Bálint and Papp, Balázs}, doi = {10.1038/s41598-022-10427-1}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {12}, unique-id = {32813213}, issn = {2045-2322}, abstract = {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.}, keywords = {AGGREGATION; PROTEINS; ASSOCIATION; GENE-EXPRESSION; PREDICTION; RATES; INTRINSIC DISORDER; Expression levels; INCLUSION-BODIES}, year = {2022}, eissn = {2045-2322}, orcid-numbers = {Őszi, Erika/0000-0002-0006-4683; Szappanos, Balázs/0000-0002-5075-1799} } @article{MTMT:32803914, title = {Gene loss and compensatory evolution promotes the emergence of morphological novelties in budding yeast}, url = {https://m2.mtmt.hu/api/publication/32803914}, author = {Farkas, Zoltán and Kovács, Károly and Sarkadi, Zsuzsa and Kalapis, Dorottya and Fekete, Gergely and Birtyik, Fanni and Ayaydin, Ferhan and Molnár, Csaba and Horváth, Péter and Pál, Csaba and Papp, Balázs}, doi = {10.1038/s41559-022-01730-1}, journal-iso = {NAT ECOL EVOL}, journal = {NATURE ECOLOGY & EVOLUTION}, volume = {6}, unique-id = {32803914}, issn = {2397-334X}, year = {2022}, eissn = {2397-334X}, pages = {763-773}, orcid-numbers = {Molnár, Csaba/0000-0002-6124-1209} } @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:32113397, title = {Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity}, url = {https://m2.mtmt.hu/api/publication/32113397}, author = {Manczinger, Máté and Koncz, Balázs and Balogh, Gergő Mihály and Papp, Benjamin Tamás and Asztalos, Leo and Kemény, Lajos and Papp, Balázs and Pál, Csaba}, doi = {10.1038/s43018-021-00226-4}, journal-iso = {NAT CANCER}, journal = {NATURE CANCER}, volume = {2}, unique-id = {32113397}, abstract = {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.}, keywords = {AFFINITY; MECHANISMS; SURVIVAL; MHC CLASS-I; PREDICTION; LUNG-CANCER; TUMOR RESPONSE; PD-1 BLOCKADE; CTLA-4 blockade}, year = {2021}, eissn = {2662-1347}, pages = {950-961}, orcid-numbers = {Kemény, Lajos/0000-0002-2119-9501} }