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Identification and prioritization of macrolideresistance genes with hypothetical annotation inStreptococcus
1Davenport University, 200 S. Grand Ave, Lansing, MI, 48933, USA.
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.
Insights
Identifying novel macrolide resistance genes in Streptococcus pneumoniae is crucial. This study highlights hypothetical genes and domains of unknown function (DUFs) that could lead to new therapies against resistant bacterial infections.
Area of Science:
- Microbiology
- Genomics
- Drug Discovery
Background:
- Macrolide-resistant Streptococcus pneumoniae poses a significant treatment challenge.
- Incomplete genome annotation, including hypothetical genes encoding domains of unknown function (DUFs), hinders understanding of resistance mechanisms.
Purpose of the Study:
- To identify and confirm macrolide resistance genes in Streptococcus pneumoniae.
- To explore DUFs within hypothetical macrolide resistance genes for prioritizing experimental characterization.
Main Methods:
- Comparative analysis of gene expression signatures between untreated and macrolide-treated resistant Streptococcus pneumoniae strains.
- Validation using independent datasets of resistant and sensitive Streptococcus pneumoniae strains.
- Functional pathway analysis of identified resistance genes.
Main Results:
- Identified gene similarities associated with macrolide resistance.
- Confirmed gene sets linked to resistance mechanisms like increased amino acid biosynthesis and efflux, and decreased ribonucleotide biosynthesis.
- Discovered 22 hypothetical genes, including 10 DUFs, associated with macrolide resistance.
Conclusions:
- Characterizing DUFs in macrolide resistance genes may reveal novel co-therapies to restore macrolide efficacy.
- The applied methodology shows predictive power and can be extended to other antibiotic resistance mechanisms.
- This research could revolutionize the treatment of resistant bacterial infections.
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