Streptococcus pneumoniae (the pneumococcus) is a major human bacterial pathogen and the leading cause of pneumonia-related deaths globally, particularly in children (≤ 5 years old) from developing countries. A diminished antibiotic pipeline and the rise in antibiotic resistant isolates highlights a need for novel or alternative strategies.
Previous work has shown that dysregulation of fundamental bacterial metal ion homeostasis can result in increased susceptibility to antimicrobial compounds. Therefore, disrupting these homeostatic pathways may represent a largely unexplored strategy that can be used to rescue the efficacy of current antibiotics. However, further investigation is needed to understand the molecular mechanisms that drive metal ion-induced susceptibility to distinct classes of antimicrobials.
Here, we investigate the use of ionophores, a class of compound that facilitates unregulated shuttling of metal ions across the bacterial cell membrane and mediates significant toxicity in S. pneumoniae. We show through in vitro broth microdilution and time-dependent killing assays, breakage of antibiotic resistance in multiple clinical isolates when antibiotics are co-administered with an ionophore. This includes breakage of macrolide resistance, restoring the efficacy of the critical, frontline antibiotic, azithromycin.
Current investigations are aiming to determine the cellular and molecular pathways facilitating this breakage of resistance and gaining better understanding of the metal homeostatic mechanisms within the pneumococcus. To this end, we will utilise a multi ‘-omic’ approach including metalloproteomics, transcriptomics, and metabolomics, and in vivo analyses in established mice models of pneumococcal infection.
Collectively, this work describes how disruption of fundamental homeostasis pathways in bacteria may provide a mechanism to restore the efficacy of our current antibiotic arsenal to combat pneumococcal infection.