Convergent evolution of antibiotic resistance mechanisms between synthetic pyrrolobenzodiazepines (PBDs) and the naturally occurring albicidin in multidrug resistant Klebsiella pneumoniae

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 the phytotoxin albicidin, specifically tsx and merR -family regulator albA . Heterologous expression of AlbA in Escherichia coli , and introduction of a proposed resistance-mediating single-nucleotide polymorphism (SNP) (AlbA L120Q) into the genome of a sensitive K. pneumoniae strain confers both PBD and albicidin resistance. 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.