@misc{MTMT:34158052, title = {Antibiotics of the future are prone to resistance in Gram-negative pathogens}, url = {https://m2.mtmt.hu/api/publication/34158052}, author = {Daruka, Lejla and Márton, Simon Czikkely and Petra, Szili and Farkas, Zoltán and Dávid, Balogh and Elvin, Maharramov and Thu-Hien, Vu and Levente, Sipos and Botond, Dávid Vincze and Gábor, Grézal and Szilvia, Juhász and Anett, Dunai and Andreea, Daraba and Mónika, Számel and Tóbiás, Sári and Tamás, Stirling and Vásárhelyi, Bálint Márk and Ari, Eszter and Chryso, Christodoulou and Máté, Manczinger and Márton, Zsolt Enyedi and Gábor, Jaksa and Stineke, van Houte and Elizabeth, Pursey and Csaba, Gergő Papp and Zóra, Szilovics and Lajos, Pintér and Lajos, Haracska and Attila, Gácser and Bálint, Kintses and Balázs, Papp and Csaba, Pál}, unique-id = {34158052}, year = {2023}, orcid-numbers = {Vásárhelyi, Bálint Márk/0000-0003-1782-8691; Ari, Eszter/0000-0001-7774-1067} } @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: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:31855890, title = {New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens}, url = {https://m2.mtmt.hu/api/publication/31855890}, author = {Durcik, M. and Nyerges, Ákos and Skok, Z and Skledar, D.G. and Trontelj, J. and Zidar, N. and Ilaš, J. and Zega, A. and Cruz, C.D. and Tammela, P. and Welin, M. and Kimbung, Y.R. and Focht, D. and Benek, O. and Révész, Tamás and Draskovits, Gábor and Szili, Petra and Daruka, Lejla and Pál, Csaba and Kikelj, D. and Mašič, L.P. and Tomašič, T.}, doi = {10.1016/j.ejmech.2021.113200}, journal-iso = {EUR J MED CHEM}, journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}, volume = {213}, unique-id = {31855890}, issn = {0223-5234}, abstract = {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}, keywords = {ANTIBACTERIAL; DNA GYRASE; benzothiazole; Topoisomerase IV; Dual inhibitor}, year = {2021}, eissn = {1768-3254}, orcid-numbers = {Nyerges, Ákos/0000-0002-1581-490X} } @article{MTMT:31642956, title = {Rational design of balanced dual-targeting antibiotics with limited resistance}, url = {https://m2.mtmt.hu/api/publication/31642956}, author = {Nyerges, Ákos and Tomasic, Tihomir and Durcik, Martina and Révész, Tamás and Szili, Petra and Draskovits, Gábor and Bogár, Ferenc and Skok, Ziga and Zidar, Nace and Ilas, Janez and Zega, Anamarija and Kikelj, Danijel and Daruka, Lejla and Kintses, Bálint and Vásárhelyi, Bálint Márk and Földesi, Imre and Kata, Diána and Welin, Martin and Kimbung, Raymond and Focht, Dorota and Masic, Lucija Peterlin and Pál, Csaba}, doi = {10.1371/journal.pbio.3000819}, journal-iso = {PLOS BIOL}, journal = {PLOS BIOLOGY}, volume = {18}, unique-id = {31642956}, issn = {1544-9173}, abstract = {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.}, year = {2020}, eissn = {1545-7885}, orcid-numbers = {Nyerges, Ákos/0000-0002-1581-490X; Tomasic, Tihomir/0000-0001-5534-209X; Bogár, Ferenc/0000-0002-0611-1452; Vásárhelyi, Bálint Márk/0000-0003-1782-8691; Földesi, Imre/0000-0002-3329-8136; Kata, Diána/0000-0002-4432-9380; Focht, Dorota/0000-0003-3373-7335} } @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} } @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:30446615, title = {New Metabolic Influencer on Oxytocin Release: The Ghrelin}, url = {https://m2.mtmt.hu/api/publication/30446615}, author = {Szabó, Renáta and Ménesi, Rudolf and Molnár, Andor and Szalai, Zita and Daruka, Lejla and Tóth, Gábor and Gardi, János and Gálfi, Márta and Börzsei, Denise and Kupai, Krisztina and Juhász, Anna and Radács, Marianna and László, Ferenc and Varga, Csaba and Pósa, Anikó}, doi = {10.3390/molecules24040735}, journal-iso = {MOLECULES}, journal = {MOLECULES}, volume = {24}, unique-id = {30446615}, issn = {1420-3049}, year = {2019}, eissn = {1420-3049}, orcid-numbers = {Molnár, Andor/0000-0001-5980-2276; Szalai, Zita/0000-0002-8722-0211; Gálfi, Márta/0000-0002-7143-133X; Kupai, Krisztina/0000-0002-0644-1718; Radács, Marianna/0000-0003-0381-9276; Varga, Csaba/0000-0002-2678-665X; Pósa, Anikó/0000-0003-2167-2888} } @article{MTMT:30434125, title = {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.}, url = {https://m2.mtmt.hu/api/publication/30434125}, author = {Bocsik, Alexandra and Gróf, Ilona and Kiss, Lóránd and Ötvös, Ferenc and Zsíros, Ottó and Daruka, Lejla and Fülöp, Lívia and Vastag, Monika and Kittel, Ágnes and Imre, Norbert and Martinek, Tamás and Pál, Csaba and Révész, Piroska and Deli, Mária Anna}, doi = {10.3390/pharmaceutics11020073}, journal-iso = {PHARMACEUTICS}, journal = {PHARMACEUTICS}, volume = {11}, unique-id = {30434125}, issn = {1999-4923}, abstract = {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.}, keywords = {Drug delivery; Claudin; Caco-2; Antimicrobial peptide; KLAL; PN159; absorption enhancer; cell-penetrating peptide (CPP); intestinal epithelial cells; tight junction modulator}, year = {2019}, eissn = {1999-4923}, orcid-numbers = {Fülöp, Lívia/0000-0002-8010-0129; Martinek, Tamás/0000-0003-3168-8066; Révész, Piroska/0000-0002-5336-6052; Deli, Mária Anna/0000-0001-6084-6524} }