Comparative genomics and functional profiling reveal lineage-specific metabolic adaptations in globally emerging fluoroquinolone-resistant Salmonella Kentucky ST198

Authors: AHMED, JUNED - Texas Tech University; SOLTYS, RACHEL - Purdue University; SHRINGI, SMRITI - Texas Tech University; GUARD, JEAN - Collaborator; Haley, Bradd; SHAH, DEVENDRA - Texas Tech University

Submitted to: Genes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/27/2025
Publication Date: 9/8/2025
Citation: Ahmed, J., Soltys, R., Shringi, S., Guard, J., Haley, B.J., Shah, D. 2025. Comparative genomics and functional profiling reveal lineage-specific metabolic adaptations in globally emerging fluoroquinolone-resistant Salmonella Kentucky ST198. Genes. 16(9). Article 1051. https://doi.org/10.3390/genes16091051.
DOI: https://doi.org/10.3390/genes16091051

Interpretive Summary: Salmonella Kentucky is a type of bacteria that has two main genetic lineages, called ST198 and ST152. ST198 is more commonly linked to human illness around the world but is rarely found in U.S. food animals. ST152 is widespread in U.S. food animals but rarely causes illness in people. Earlier research showed that these two types of Salmonella Kentucky have different sets of genetic mutations, suggesting that they evolved in different ways. These changes most likely affect how these two types grow, how infectious they are, and how well they adapt to surviving and replicating in animals and people. In this study, researchers sought to understand how these genetic differences affect Salmonella Kentucky’s ability to utilize different nutrients. Seven strains were chosen to evaluate the utilization of and persistence in 949 different substrates and conditions. ST198 was able to better utilize two nutrients found in gut, lactulose and myo-inositol. Closer examination of the genomes of these organisms revealed that ST198 strains had genes for utilizing these nutrients and ST152 did not have these genes. Overall, the findings suggest that ST198 has unique abilities to persist in the gut, making it more likely to spread and cause disease compared to ST152. Understanding the traits that make certain Salmonella strains more likely to spread between animals and cause disease in humans can help improve food safety by guiding better detection, prevention, and control strategies and therefore protecting consumers from infections and producers from costly outbreaks and recalls.

Technical Abstract: Salmonella Kentucky comprises two major lineages, ST152 and fluoroquinolone-resistant (FluR) ST198, which have diverged genotypically and phenotypically along distinct evolutionary and epidemiological trajectories. ST198 is linked to global human disease, while ST152 is primarily animal-associated in the U.S. We hypothesized that lineage-specific metabolic adaptations contribute to their differing host associations and pathogenicity. Methods: We performed comparative metabolic profiling of ST198 (n = 3) and ST152 (n = 4) strains across 948 substrates and environmental conditions. Growth assays tested the ability of these lineages and other non-typhoidal Salmonella (NTS) serovars (n = 5) to utilize myo-inositol and lactulose as sole carbon sources. Comparative genomic analyses of 294 ST198, 173 ST152, and 1300 other NTS serovars identified nutrient utilization genes. Results: ST198 exhibited significantly higher respiratory activity and broader metabolic versatility across carbon, nitrogen/sulfur sources, and stress conditions. The canonical iol gene cluster for myo-inositol catabolism was conserved in ST198 but absent in ST152, which nonetheless showed weak growth on myo-inositol, suggesting an alternative metabolic pathway for myo-inositol may exist. We also report for the first time that, despite lineage-specific differences in metabolic efficiency, multiple NTS serovars, including S. Kentucky, can metabolize lactulose, a synthetic disaccharide traditionally associated with beneficial gut microbes. These results suggest the potential existence of a novel lactulose metabolic pathway in NTS. Conclusions: These findings highlight ST198’s metabolic adaptability and reveal novel metabolic capacities in NTS. A mechanistic understanding of nutrient utilization pathways, particularly of myo-inositol and lactulose, will provide novel insights into the mechanisms underlying nutrient metabolism that likely modulate the ecological success and pathogenic potential of NTS in human and animal hosts.