The Effect of Impaired Polyamine Transport on Pneumococcal Transcriptome.

Mary Nakamya,Leslie Shack,Moses Ayoola,Edwin Swiatlo,Bindu Nanduri

doi:10.3390/pathogens10101322

Mary Nakamya, Leslie Shack + Show 3 more

Open Access

https://doi.org/10.3390/pathogens10101322

Copy DOI

Abstract

Infections due to Streptococcus pneumoniae, a commensal in the nasopharynx, still claim a significant number of lives worldwide. Genome plasticity, antibiotic resistance, and limited serotype coverage of the available polysaccharide-based conjugate vaccines confounds therapeutic interventions to limit the spread of this pathogen. Pathogenic mechanisms that allow successful adaption and persistence in the host could be potential innovative therapeutic targets. Polyamines are ubiquitous polycationic molecules that regulate many cellular processes. We previously reported that deletion of polyamine transport operon potABCD, which encodes a putrescine/spermidine transporter (ΔpotABCD), resulted in an unencapsulated attenuated phenotype. Here, we characterize the transcriptome, metabolome, and stress responses of polyamine transport-deficient S. pneumoniae. Compared with the wild-type strain, the expression of genes involved in oxidative stress responses and the nucleotide sugar metabolism was reduced, while expression of genes involved in the Leloir, tagatose, and pentose phosphate pathways was higher in ΔpotABCD. A metabolic shift towards the pentose phosphate pathway will limit the synthesis of precursors of capsule polysaccharides. Metabolomics results show reduced levels of glutathione and pyruvate in the mutant. Our results also show that the potABCD operon protects pneumococci against hydrogen peroxide and nitrosative stress. Our findings demonstrate the importance of polyamine transport in pneumococcal physiology that could impact in vivo fitness. Thus, polyamine transport in pneumococci represents a novel target for therapeutic interventions.

Highlights

Despite years of intensive research, infections due to Streptococcus pneumoniae still claim countless lives across the globe [1]
Our results show that impaired polyamine transport renders pneumococci susceptible to stress and shifts central metabolism towards the pentose phosphate pathway (PPP), which could adversely affect the synthesis of precursors for capsular polysaccharide
Findings in this study show that a deficiency in polyamine transport impairs pneumococcal stress responses and shifts central metabolism towards the PPP

Summary

Introduction

Despite years of intensive research, infections due to Streptococcus pneumoniae (pneumococcus) still claim countless lives across the globe [1]. Pneumococci account for up to 15% of pneumonia cases in the USA and 27% worldwide [2]. Following colonization of the nasopharynx, pneumococci can translocate to sterile sites and cause infections such as otitis media, community-acquired pneumonia, meningitis, and septicemia [3]. Well-coordinated metabolic networks for efficient exploitation of the host micro-nutrients and immune response evasion strategies are crucial for pneumococcal pathogenesis. Serotype diversity, limited serotype coverage of the available vaccines, serotype replacement, and increase in multidrug-resistant strains confound intervention strategies that limit the spread of pneumococci [4,5,6]. A better understanding of pneumococcal physiology and survival mechanisms in the host can identify novel therapeutic targets

Methods

Results

Conclusion