Convergent evolution of antibiotic resistance mechanisms between pyrrolobenzodiazepines and albicidin in multidrug resistant Klebsiella pneumoniae
Pyrrolobenzodiazepines (PBDs) containing C8-linked aliphatic heterocycles have been developed as a new class of potent antibacterial compounds. They are active against multidrug resistant Gram-negative pathogens, including Klebsiella pneumoniae. When isolates were exposed to PBDs, they acquired resistance, with significant increases in inhibitory concentrations. Resistant strains showed mutations in genes associated with resistance to albicidin, specifically tsx and merR-family regulator albA. Heterologous expression of AlbA in E. coli and introducing the L120Q AlbA resistance-mediating modification into the genome of a sensitive K. pneumoniae strain conferred PBD and albicidin resistance. Proteomic analysis of the resistant strains showed elevated AlbA protein levels compared to isogenic wild-type strains. Crystallographic studies with the antibiotic binding domain of AlbA show binding of KMR-14-14 to the same groove shown to bind albicidin. Given the parallels between these two structurally unrelated compound classes, AlbA may offer resistance to further antibiotics and should be considered in future antibiotic discovery.
Authors
- Khondaker Miraz Rahman (ORCID: https://orcid.org/0000-0001-8566-8648)
- Michael Maynard-Smith
- Roberto A. Steiner (ORCID: https://orcid.org/0000-0001-7084-9745)
- Kazi S. Nahar (ORCID: https://orcid.org/0000-0002-1496-4455)
- Roderich D. Süßmuth (ORCID: https://orcid.org/0000-0001-7027-2069)
- Md. Mahbub Hasan (ORCID: https://orcid.org/0000-0002-5769-5224)
- Paolo Andriollo (ORCID: https://orcid.org/0009-0006-3754-6877)
- Riccardo Zenezini Chiozzi (ORCID: https://orcid.org/0000-0003-3904-5532)
- S. Gratz
- Charlotte K. Hind (ORCID: https://orcid.org/0000-0002-3763-3106)
- Matthew E. Wand (ORCID: https://orcid.org/0000-0002-9277-8869)
- Yasmin M. Surani (ORCID: https://orcid.org/0000-0002-6991-8739)
- J. Mark Sutton (ORCID: https://orcid.org/0000-0002-2288-0446)
- Michele Di Palma (ORCID: https://orcid.org/0000-0002-0710-9389)
- Pietro Picconi
Institutions
- Defence Science and Technology Laboratory (GB)
- University of Padua (IT)
- King's College London (GB)
- Department of Science and Technology (IN)
- University College London (GB)
- Technische Universität Berlin (DE)
- University of Chittagong (BD)
Publication Details
- Journal
- npj Antimicrobials and Resistance
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1038/s44259-025-00104-4
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute for Health and Care Research
- Department of Health and Social Care
- Commonwealth Scholarship Commission
- European Synchrotron Radiation Facility
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università degli Studi di Padova
- Ministero dell'Università e della Ricerca
- Biotechnology and Biological Sciences Research Council