Daruka, Lejla and Czikkely, Márton Simon and Szili, Petra and Farkas, Zoltán and Balogh, Dávid and Grézal, Gábor and Maharramov, Elvin and Vu, Thu-Hien and Sipos, Levente and Juhász, Szilvia and Dunai, Anett and Daraba, Andreea and Számel, Mónika and Sári, Tóbiás and Stirling, Tamás and Vásárhelyi, Bálint Márk and Ari, Eszter and Christodoulou, Chryso and Manczinger, Máté and Enyedi, Márton Zsolt and Jaksa, Gábor and Kovács, Károly and van Houte, Stineke and Pursey, Elizabeth and Pintér, Lajos and Haracska, Lajos and Kintses, Bálint and Papp, Balázs and Pál, Csaba (2025) ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro. NATURE MICROBIOLOGY, 10 (2). pp. 313-331. ISSN 2058-5276
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Abstract
Despite ongoing antibiotic development, evolution of resistance may render candidate antibiotics ineffective. Here we studied in vitro emergence of resistance to 13 antibiotics introduced after 2017 or currently in development, compared with in-use antibiotics. Laboratory evolution showed that clinically relevant resistance arises within 60 days of antibiotic exposure in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, priority Gram-negative ESKAPE pathogens. Resistance mutations are already present in natural populations of pathogens, indicating that resistance in nature can emerge through selection of pre-existing bacterial variants. Functional metagenomics showed that mobile resistance genes to antibiotic candidates are prevalent in clinical bacterial isolates, soil and human gut microbiomes. Overall, antibiotic candidates show similar susceptibility to resistance development as antibiotics currently in use, and the corresponding resistance mechanisms overlap. However, certain combinations of antibiotics and bacterial strains were less prone to developing resistance, revealing potential narrow-spectrum antibacterial therapies that could remain effective. Finally, we develop criteria to guide efforts in developing effective antibiotic candidates.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: European Research Council; National Laboratory of Biotechnology Grant [2022-2.1.1-NL-2022-00008]; National Research Development and Innovation Office 'Elvonal' Programme KKP [126506]; National Research, Development and Innovation Office [K146323, FK-135245, RRF-2.3.1-21-2022-00015, TKP-31-8/PALY-2021]; National Research, Development and Innovation Office 'Elvonal' program KKP [KH125616]; National Laboratory for Health Security [RRF-2.3.1-21-2022-00006]; European Union [739593]; Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences [BO/352/20, bo_656_20]; New National Excellence Program of the Ministry of Human Capacities; Proof-of-Concept grant of the Eoetvoes Lorand Research Network [ELKH-PoC-2022-034]; New National Excellence Program of the Ministry for Culture and Innovation [UNKP-22-2-SZTE-220, UNKP-23-3-SZTE-272]; National Academy of Scientist Education under the sponsorship of the Hungarian Ministry of Culture and Innovation; University Research Scholarship Program Grant under the sponsorship of the Hungarian Ministry of Culture and Innovation [EKOEP-KDP-24-SZTE-13]; National Research, Development and Innovation Office, Hungary (NKFIH) [131839, FK-142312, FK-131961]; National Research, Development and Innovation Office, Hungary (NKFIH) KIM NKFIA [TKP-2021-EGA-05, 2022-2.1.1-NL-2022-00005, H2020-WIDESPREA-01-2016-2017-TeamingPhase2, 739593-HCEMM]; New National Excellence Program of the Ministry of Human Capacities Bolyai+ [UNKP-22-5-SZTE-578-Bolyai+]; Lister Institute for Preventative Medicine; [ERC-2023-ADG 101142626]; [UNKP-20-5-SZTE-654]; [UNKP-21-5-SZTE-579] Funding text: We thank A. Kobl for her help with illustrations in Extended Data Fig. 1. This work was supported by The European Research Council ERC-2023-ADG 101142626 FutureAntibiotics (C.P.); The National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P., B.K. and B.P.); National Research Development and Innovation Office 'Elvonal' Programme KKP 126506 (C.P.); National Research, Development and Innovation Office K146323 (C.P.); National Research, Development and Innovation Office 'Elvonal' program KKP KH125616 (B.P.); The National Laboratory for Health Security RRF-2.3.1-21-2022-00006 (B.P.); The European Union's Horizon 2020 research and innovation programme under grant agreement number 739593 (B.K., B.P. and M.M.); National Research, Development and Innovation Office grant FK-135245 (B.K.); Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences (BO/352/20; B.K.); New National Excellence Program of the Ministry of Human Capacities (UNKP-20-5-SZTE-654 and UNKP-21- 5-SZTE-579; B.K.); Proof-of-Concept grant of the Eoetvoes Lorand Research Network (ELKH-PoC-2022-034; B.K.); The New National Excellence Program of the Ministry for Culture and Innovation (UNKP-22-2-SZTE-220 and UNKP-23-3-SZTE-272; M.S.C.); The National Academy of Scientist Education under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.S.C.); University Research Scholarship Program Grant under the sponsorship of the Hungarian Ministry of Culture and Innovation (EKOEP-KDP-24-SZTE-13; M.S.C.); The National Research, Development and Innovation Office, Hungary (NKFIH) grant PD, grant number 131839 (E.A.); The National Research, Development and Innovation Office, Hungary (NKFIH) grant FK-142312 (M.M.); The National Research, Development and Innovation Office, Hungary (NKFIH) KIM NKFIA TKP-2021-EGA-05 (S.J.); The National Research, Development and Innovation Office, Hungary (NKFIH) KIM NKFIA 2022-2.1.1-NL-2022-00005 (S.J.); H2020-WIDESPREA-01-2016-2017-TeamingPhase2, GA:739593-HCEMM (S.J.); The National Research, Development and Innovation Office, Hungary (NKFIH) grant FK-131961 (S.J.); The New National Excellence Program of the Ministry of Human Capacities Bolyai+, UNKP-22-5-SZTE-578-Bolyai+ (S.J.); The Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences bo_656_20 (S.J.); The Lister Institute for Preventative Medicine (S.v.H.); and The National Research, Development and Innovation Office (PharmaLab, RRF-2.3.1-21-2022-00015 and TKP-31-8/PALY-2021; L.H.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QR Microbiology / mikrobiológia R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 10 Feb 2026 12:50 |
| Last Modified: | 10 Feb 2026 12:50 |
| URI: | https://real.mtak.hu/id/eprint/233655 |
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