Abstract
Macrolide resistant Streptococcus pneumoniae infections have limited treatment options. While some resistance mechanisms are well established, ample understanding is limited by incomplete genome annotation (hypothetical genes). Some hypothetical genes encode a domain of unknown function (DUF), a conserved protein domain with uncharacterized function. Here, we identify and confirm macrolide resistance genes. We further explore DUFs from macrolide resistance hypothetical genes to prioritize them for experimental characterization. We found gene similarities between two macrolide resistance gene signatures from untreated and either erythromycin- or spiramycin-treated resistant Streptococcus pneumoniae. We confirmed the association of these gene sets with macrolide resistance through comparison to gene signatures from (i) second erythromycin resistant Streptococcus pneumoniae strain, and (ii) erythromycin-treated sensitive Streptococcus pneumoniae strain, both from non-overlapping datasets. Examination into which cellular processes these macrolide resistance genes belong found connections to known resistance mechanisms such as increased amino acid biosynthesis and efflux genes, and decreased ribonucleotide biosynthesis genes, highlighting the predictive ability of the method used. 22 genes had hypothetical annotation with 10 DUFs associated with macrolide resistance. DUF characterization could uncover novel co-therapies that restore macrolide efficacy across multiple macrolide resistant species. Application of the methods to other antibiotic resistances could revolutionize treatment of resistant infections
Highlights
Streptococcus pneumoniae (S. pneumoniae) infections cause approximately 1.2 million life-threatening illnesses resulting in 7,000 deaths annually including bacterial upper respiratory infections and pneumonia and meningitis, and bloodstream, ear, and sinus infections [1, 2]
Through we introduce this approach while exploring erythromycin resistant S. pneumoniae, recommendations provided by applying our approach to other antibiotic resistant bacterial infections can reduce development costs and time to availability for potential new co-therapy targets, substantially renovating the way antibiotic resistant infections are treated clinically
Similarities between erythromycin and spiramycin signatures reveal genes associated with macrolide resistance To identify genes associated with macrolide resistance, we compared erythromycin and spiramycin gene expression signatures with the idea that genes with similar differential expression when erythromycin resistant S. pneumoniaeis treated with different macrolides are associated with macrolide resistance
Summary
Streptococcus pneumoniae (S. pneumoniae) infections cause approximately 1.2 million life-threatening illnesses resulting in 7,000 deaths annually including bacterial upper respiratory infections and pneumonia and meningitis, and bloodstream, ear, and sinus infections [1, 2]. We identify and validate genes associated with macrolide resistance by comparing therapeutic response gene expression signatures (list of genes ranked from high to low differential expression between untreated and macrolide treated samples) in S. pneumonia (Figure 1). To confirm that identified leading-edge genes are related to resistance, we (i) used leading-edge genes as query gene sets for GSEA with a T-ranked erythromycin response signature from a macrolide sensitive strain (XZ8009) as reference, and (ii) utilized Principal Component Analysis (PCA) and Leave One Out Cross Validation (LOOCV) to examine expression of leading-edge genes in another macrolide resistant strain, XZ7022 (Figure 1). Symbols for all leading-edge genes without exception were included in GO analysis
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