Frontiers in medicine · 2026
Genome-informed metabolomic re-analysis identifies serum-associated amino acid signatures in sepsis-associated bacterial pathogens.
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Ou Min, Luo Yulan, Sun Xiaopeng, Luo Shifeng, Feng Mei
Аннотация
BACKGROUND: Antibiotic-resistant bacterial infections remain a major global health threat, particularly in hospital settings. Standard antimicrobial susceptibility testing provides essential clinical information, but it does not fully capture pathogen metabolic adaptation under host-like conditions. Integrating isolate whole-genome sequencing with metabolomics may help prioritize condition-associated metabolic signatures linked to bacterial physiology and antibiotic response.
METHODS: We performed a secondary integrative re-analysis of publicly available isolate whole-genome sequencing and matched metabolomics datasets from Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes cultured under RPMI and human serum conditions. Genome assemblies were assessed by quality metrics, fastANI, functional annotation, antimicrobial resistance gene screening, virulence-factor analysis, and KEGG profiling. Metabolomics data were analyzed using PCA, OPLS-DA, KEGG enrichment, and ROC analysis for exploratory feature prioritization. Candidate metabolites were further evaluated in Klebsiella quasipneumoniae ATCC 700603 cultured under RPMI or heat-inactivated human serum conditions.
RESULTS: Metabolomic profiles showed condition-associated separation between RPMI and serum samples, with the most consistent serum-associated signature observed in Klebsiella. KEGG enrichment prioritized amino acid metabolism, particularly valine, leucine and isoleucine biosynthesis and alanine, aspartate and glutamate metabolism. l-aspartic acid, l-isoleucine, l-leucine, and l-valine showed strong within-dataset discriminatory performance in Klebsiella. Experimental validation showed that serum exposure reduced Klebsiella growth and viable bacterial burden, increased cell-associated levels of these amino acids, and elevated meropenem and ciprofloxacin MIC-like inhibitory endpoints under serum-conditioned assay conditions.
CONCLUSION: This integrative re-analysis identified serum-associated amino acid remodeling as a prominent feature of host-like adaptation in Klebsiella. These findings provide candidate metabolic signatures for future mechanistic validation and suggest that serum exposure is associated with growth restriction and reduced antibiotic susceptibility under host-like conditions.
METHODS: We performed a secondary integrative re-analysis of publicly available isolate whole-genome sequencing and matched metabolomics datasets from Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes cultured under RPMI and human serum conditions. Genome assemblies were assessed by quality metrics, fastANI, functional annotation, antimicrobial resistance gene screening, virulence-factor analysis, and KEGG profiling. Metabolomics data were analyzed using PCA, OPLS-DA, KEGG enrichment, and ROC analysis for exploratory feature prioritization. Candidate metabolites were further evaluated in Klebsiella quasipneumoniae ATCC 700603 cultured under RPMI or heat-inactivated human serum conditions.
RESULTS: Metabolomic profiles showed condition-associated separation between RPMI and serum samples, with the most consistent serum-associated signature observed in Klebsiella. KEGG enrichment prioritized amino acid metabolism, particularly valine, leucine and isoleucine biosynthesis and alanine, aspartate and glutamate metabolism. l-aspartic acid, l-isoleucine, l-leucine, and l-valine showed strong within-dataset discriminatory performance in Klebsiella. Experimental validation showed that serum exposure reduced Klebsiella growth and viable bacterial burden, increased cell-associated levels of these amino acids, and elevated meropenem and ciprofloxacin MIC-like inhibitory endpoints under serum-conditioned assay conditions.
CONCLUSION: This integrative re-analysis identified serum-associated amino acid remodeling as a prominent feature of host-like adaptation in Klebsiella. These findings provide candidate metabolic signatures for future mechanistic validation and suggest that serum exposure is associated with growth restriction and reduced antibiotic susceptibility under host-like conditions.