TY - JOUR AU - Bognár, Bence AU - Spohn, Réka AU - Lázár, Viktória TI - Drug combinations targeting antibiotic resistance JF - npj Antimicrobials and Resistance J2 - npj Antimicrob Resist VL - 2 PY - 2025 IS - 1 SN - 2731-8745 DO - 10.1038/s44259-024-00047-2 UR - https://m2.mtmt.hu/api/publication/35470389 ID - 35470389 LA - English DB - MTMT ER - TY - JOUR AU - Maharramov, Elvin AU - Czikkely, Márton Simon AU - Szili, Petra AU - Farkas, Zoltán AU - Grézal, Gábor AU - Daruka, Lejla AU - Kurkó, Eszter AU - Mészáros, Léna AU - Daraba, Andreea AU - Kovacs, Terezia AU - Bognár, Bence AU - Juhász, Szilvia AU - Papp, Balázs AU - Lázár, Viktória AU - Pál, Csaba TI - Exploring the principles behind antibiotics with limited resistance JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 16 PY - 2025 IS - 1 PG - 18 SN - 2041-1723 DO - 10.1038/s41467-025-56934-3 UR - https://m2.mtmt.hu/api/publication/35780670 ID - 35780670 N1 - Synthetic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre Szeged, Szeged, Hungary Doctoral School of Biology, University of Szeged, Szeged, Hungary Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary Department of Forensic Medicine, Albert-Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary HCEMM-BRC Metabolic Systems Biology Group, Szeged, Hungary Hungarian Centre of Excellence for Molecular Medicine, Cancer Microbiome Core Group, Budapesti út 9, Szeged, Hungary HCEMM-BRC Pharmacodynamic Drug Interaction Research Group, Szeged, Hungary Export Date: 6 March 2025 Correspondence Address: Pál, C.; Synthetic and Systems Biology Unit, Hungary; email: cpal@brc.hu AB - Antibiotics that target multiple cellular functions are anticipated to be less prone to bacterial resistance. Here we hypothesize that while dual targeting is crucial, it is not sufficient in preventing resistance. Only those antibiotics that simultaneously target membrane integrity and block another cellular pathway display reduced resistance development. To test the hypothesis, we focus on three antibiotic candidates, POL7306, Tridecaptin M152-P3 and SCH79797, all of which fulfill the above criteria. Here we show that resistance evolution against these antibiotics is limited in ESKAPE pathogens, including Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumannii and Pseudomonas aeruginosa , while dual-target topoisomerase antibiotics are prone to resistance. We discover several mechanisms restricting resistance. First, de novo mutations result in only a limited elevation in resistance, including those affecting the molecular targets and efflux pumps. Second, resistance is inaccessible through gene amplification. Third, functional metagenomics reveal that mobile resistance genes are rare in human gut, soil and clinical microbiomes. Finally, we detect rapid eradication of bacterial populations upon toxic exposure to membrane targeting antibiotics. We conclude that resistance mechanisms commonly found in natural bacterial pathogens provide only limited protection to these antibiotics. Our work provides guidelines for the future development of antibiotics. LA - English DB - MTMT ER - TY - JOUR AU - Szatmári, Orsolya AU - Nagy-Mikó, Bence AU - Györkei, Ádám AU - Varga, Dániel AU - H. Kovács, Bálint Barna AU - Igaz, Nóra AU - Bognár, Bence AU - Rázga, Zsolt AU - Nagy, Gábor AU - Zsindely, Nóra AU - Bodai, László AU - Papp, Balázs AU - Erdélyi, Miklós AU - Csontné Kiricsi, Mónika AU - Blastyák, András AU - Collart, Martine A AU - Boros, Imre Miklós AU - Villanyi, Zoltan TI - Phase-separated ribosome-nascent chain complexes in genotoxic stress response JF - RNA-A PUBLICATION OF THE RNA SOCIETY J2 - RNA VL - 29 PY - 2023 IS - 10 SP - 1557 EP - 1574 PG - 18 SN - 1355-8382 DO - 10.1261/rna.079755.123 UR - https://m2.mtmt.hu/api/publication/34067381 ID - 34067381 N1 - Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, 6726, Hungary Institute of Biochemistry, Biological Research Centre, Szeged, 6726, Hungary Section for Physiology and Cell Biology, Department of Biosciences, University of Oslo, Oslo, 0316, Norway Department of Optics and Quantum Electronics, University of Szeged, Szeged, 6720, Hungary Department of Pathology, Faculty of Medicine, University of Szeged, Szeged, 6720, Hungary Institute of Genetics, Biological Research Centre, Szeged, 6726, Hungary Department of Microbiology and Molecular Medicine, Institute of Genetics and Genomics Geneva, Faculty of Medicine, University of Geneva, Geneva 4, 1211, Switzerland Cited By :1 Export Date: 12 December 2023 CODEN: RNARF Correspondence Address: Villányi, Z.; Department of Biochemistry and Molecular Biology, Hungary; email: villanyi.zoltan@bio.u-szeged.hu Chemicals/CAS: 1,6 hexanediol, 629-11-8; DNA helicase; edetic acid, 150-43-6, 60-00-4; ribonuclease, 59794-03-5, 9001-99-4; transcriptional regulator ATRX; Werner syndrome ATP dependent helicase; RNA, 63231-63-0; Edetic Acid; RecQ Helicases; Ribonucleoproteins; RNA; Saccharomyces cerevisiae Proteins; SGS1 protein, S cerevisiae Funding details: 31003A_172999, NTP-NFTÖ-20-B-0354 Funding details: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF Funding details: Magyar Tudományos Akadémia, MTA, BO/00878/19/8, BO/902/19, TKP2021-NVA-19 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI Funding text 1: We are grateful to Dr. Balázs Vedelek and Dr. Zsuzsa Sarkadi for valuable discussions. We thank Jawad Iqbal, Elvira Czvik, Zita Kóra, and Edina Pataki for technical assistance. We are grateful to Blanka Léhy for the graphical abstract. This work was supported by grants GINOP-2.3.2-15-2016-00020 and GINOP-2.3.2-15-2016-00038, as well as by NKFI-K 142961 (Z.V.), ÚNKP-21-5-595-SZTE (Z.V.), and ÚNKP-20-5-SZTE-655 (M.K.) from the Hungarian National Research, Development and Innovation Office. Further support was provided by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/902/19 for Z.V. and BO/00878/19/8 for M.K.). Superresolu-tion dSTORM experiments and their evaluation were funded by the Hungarian National Research, Development and Innovation Office (TKP2021-NVA-19), Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002) awarded to M.E., and NTP-NFTÖ-20-B-0354 awarded to D.V., as well as grant 31003A_172999 from the Swiss National Science Foundation awarded to M.A.C. AB - Assemblysomes are EDTA- and RNase-resistant ribonucleoprotein (RNP) complexes of paused ribosomes with protruding nascent polypeptide chains. They have been described in yeast and human cells for the proteasome subunit Rpt1, and the disordered N-terminal part of the nascent chain was found to be indispensable for the accumulation of the Rpt1-RNP into assemblysomes. Motivated by this, to find other assemblysome-associated RNPs we used bioinformatics to rank subunits of Saccharomyces cerevisiae protein complexes according to their N-terminal disorder propensity. The results revealed that gene products involved in DNA repair are enriched among the top candidates. The Sgs1 DNA helicase was chosen for experimental validation. We found that indeed nascent chains of Sgs1 form EDTA-resistant RNP condensates, assemblysomes by definition. Moreover, upon exposure to UV, SGS1 mRNA shifted from assemblysomes to polysomes, suggesting that external stimuli are regulators of assemblysome dynamics. We extended our studies to human cell lines. The BLM helicase, ortholog of yeast Sgs1, was identified upon sequencing assemblysome-associated RNAs from the MCF7 human breast cancer cell line, and mRNAs encoding DNA repair proteins were overall enriched. Using the radiation-resistant A549 cell line, we observed by transmission electron microscopy that 1,6-hexanediol, an agent known to disrupt phase-separated condensates, depletes ring ribosome structures compatible with assemblysomes from the cytoplasm of cells and makes the cells more sensitive to X-ray treatment. Taken together these findings suggest that assemblysomes may be a component of the DNA damage response from yeast to human. LA - English DB - MTMT ER - TY - JOUR AU - Nagy-Mikó, Bence AU - Szatmári, Orsolya AU - Faragó-Mészáros, Réka AU - Csókási, Aliz AU - Bognár, Bence AU - Ördög, Nóra AU - Borsos, Barbara Nikolett AU - Majoros, Hajnalka AU - Újfaludi, Zsuzsanna AU - Oláh, Orsolya AU - Nikolényi, Alíz AU - Dobi, Ágnes AU - Kószó, Renáta Lilla AU - Sántha, Dóra AU - Lázár, György ifj AU - Simonka, Zsolt AU - Paszt, Attila AU - Ormándi, Katalin AU - Pankotai, Tibor AU - Boros, Imre Miklós AU - Villanyi, Zoltan AU - Vörös, András TI - Predictive Potential of RNA Polymerase B (II) Subunit 1 (RPB1) Cytoplasmic Aggregation for Neoadjuvant Chemotherapy Failure JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 21 PG - 9 SN - 1661-6596 DO - 10.3390/ijms242115869 UR - https://m2.mtmt.hu/api/publication/34230980 ID - 34230980 AB - We aimed to investigate the contribution of co-translational protein aggregation to the chemotherapy resistance of tumor cells. Increased co-translational protein aggregation reflects altered translation regulation that may have the potential to buffer transcription under genotoxic stress. As an indicator for such an event, we followed the cytoplasmic aggregation of RPB1, the aggregation-prone largest subunit of RNA polymerase II, in biopsy samples taken from patients with invasive carcinoma of no special type. RPB1 frequently aggregates co-translationally in the absence of proper HSP90 chaperone function or in ribosome mutant cells as revealed formerly in yeast. We found that cytoplasmic foci of RPB1 occur in larger sizes in tumors that showed no regression after therapy. Based on these results, we propose that monitoring the cytoplasmic aggregation of RPB1 may be suitable for determining—from biopsy samples taken before treatment—the effectiveness of neoadjuvant chemotherapy. LA - English DB - MTMT ER -