PBT2 potentiates carbapenem antibiotics against diverse Klebsiella pneumoniae strains
TL;DR
The data show that zinc and PBT2 can increase the sensitivity of diverse clinical strains of K. pneumoniae to carbapenem antibiotics, and suggest that PBT2 may have potential as an adjunct therapy for the treatment of multidrug-resistant K. pneumoniae.
Abstract
ABSTRACT Carbapenem-resistant Klebsiella pneumoniae is recognized by the World Health Organization as a critical priority for urgent antimicrobial development. Due to the lack of novel antimicrobial classes in the development pipeline, this study investigated the application of an antibiotic potentiator, the zinc ionophore PBT2, to restore the utility of critical antibiotics. The data show that zinc and PBT2 can increase the sensitivity of diverse clinical strains of K. pneumoniae to carbapenem antibiotics, including those strains containing metallo-β-lactamases and porin mutations. PBT2 induced zinc and iron dyshomeostasis in these strains, resulting in altered uptake of multiple antimicrobial agents. Furthermore, PBT2 exposure also decreased resistance to agents, including ethanol and hydrogen peroxide, and reduced the potential for horizontal gene mobilization. Collectively, these impacts on metal homeostasis and cell composition suggest that PBT2 may have potential as an adjunct therapy for the treatment of multidrug-resistant K. pneumoniae. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is a major nosocomial threat and a top World Health Organization priority for urgent antimicrobial development. Resistance can be mediated by multiple classes of mobilizable carbapenemase enzymes, with varied treatment recommendations, depending on which class is present. This work describes how a repurposed drug called PBT2 can potentiate carbapenem activity against a clinical K. pneumoniae panel, independent of resistance mechanism. This could support the development of PBT2 as a broad-spectrum potentiator compound against drug-resistant K. pneumoniae. Carbapenem-resistant Klebsiella pneumoniae is a major nosocomial threat and a top World Health Organization priority for urgent antimicrobial development. Resistance can be mediated by multiple classes of mobilizable carbapenemase enzymes, with varied treatment recommendations, depending on which class is present. This work describes how a repurposed drug called PBT2 can potentiate carbapenem activity against a clinical K. pneumoniae panel, independent of resistance mechanism. This could support the development of PBT2 as a broad-spectrum potentiator compound against drug-resistant K. pneumoniae.