PXD059600-1

PXD059600 is an original dataset announced via ProteomeXchange.

Title	Convergent evolution of antibiotic resistance mechanisms between synthetic pyrrolobenzodiazepines (PBDs) and the naturally occurring albicidin in multidrug resistant Klebsiella pneumoniae
Description	Klebsiella pneumoniae is designated as one of six priority ESKAPE pathogens by the World Health Organisation (WHO). It is the causative agent of a number of serious infections, including pneumonia, and worryingly strains are known to have resistance to the four major antibiotic classes. Pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic heterocycle have been developed as a new class of potent antibacterial compounds. They are active against multidrug resistant (MDR) Gram-negative pathogens, including K. pneumoniae. When K. pneumoniae isolates were exposed to PBDs, they acquired resistance, with an increase in minimum inhibitory concentration (MIC) from 1-4 µg/mL to >32 µg/mL. Resistant strains showed mutations in genes associated with resistance to albicidin, a natural antimicrobial produced by Xanthomonas albilineans, specifically tsx and merR-family regulator albA. Heterologous expression of AlbA in Escherichia coli, and introduction of a proposed resistance-mediating single-nucleotide modification (AlbA L120Q) into the genome of a sensitive K. pneumoniae strain confers both PBD and albicidin resistance. This is further supported by proteomic analysis of the recombineered K. pneumoniae strain (NCTC 7427 AlbA L120Q) together with two strains that have acquired PBD resistance (NCTC 13438 AlbA L120Q and NCTC 13368 AlbA H50N), which all show significantly elevated levels of the AlbA protein compared to isogenic wild-type strains. Crystallographic studies with the purified antibiotic binding domain of K. oxytoca AlbA (termed AlbAS) show binding of KMR-14-14 to the same groove which has been previously shown to bind albicidin, but with a stoichiometry of two PBD bound to each molecule of AlbAS protein. Given the parallels between these two structurally unrelated compound classes, these mechanisms may offer resistance to further antibiotics in K. pneumoniae and should be considered in future antibiotic discovery.
HostingRepository	PRIDE
AnnounceDate	2025-06-16
AnnouncementXML	Submission_2025-06-15_16:13:10.554.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	riccardo zenezini chiozzi
SpeciesList	scientific name: Klebsiella pneumoniae subsp. pneumoniae A; NCBI TaxID: 1417983;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-09 09:22:22	ID requested
⏵ 1	2025-06-15 16:13:11	announced

Surani YM, Wand ME, Picconi P, Di Palma M, Zenezini Chiozzi R, Hasan MM, Andriollo P, Gr, ä, tz S, Nahar KS, Maynard-Smith M, S, ü, ssmuth RD, Steiner RA, Rahman KM, Hind CK, Sutton JM, Convergent evolution of antibiotic resistance mechanisms between pyrrolobenzodiazepines and albicidin in multidrug resistant Klebsiella pneumoniae. NPJ Antimicrob Resist, 3(1):52(2025) [pubmed]

10.1038/s44259-025-00104-4;

submitter keyword: multidrug resistance, pyrrolobenzodiazepines (PBDs),Klebsiella pneumoniae, Gram-negative bacteria, albicidin, antimicrobial resistance

Kostantinos Thalassinos
contact affiliation	Institute of Structural and Molecular Biology, Division of Biosciences, Darwin Building, University College London, Gower Street, London WC1E 6BT, United Kingdom
contact email	k.thalassinos@ucl.ac.uk
lab head
riccardo zenezini chiozzi
contact affiliation	UCL
contact email	r.chiozzi@ucl.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/06/PXD059600

PRIDE project URI

• PRIDE
  1. PXD059600
     1. Label: PRIDE project
     2. Name: Convergent evolution of antibiotic resistance mechanisms between synthetic pyrrolobenzodiazepines (PBDs) and the naturally occurring albicidin in multidrug resistant Klebsiella pneumoniae