A metabolic atlas of the Klebsiella pneumoniae species complex reveals lineage-specific metabolism that supports persistent co-existence of diverse lineages

The Klebsiella pneumoniae species complex inhabits a wide variety of hosts and environments, and is a major cause of antimicrobial resistant infections. Genomics has revealed the population comprises multiple species/subspecies and hundreds of distinct co-circulating sub-lineages that are associated with distinct gene complements. A substantial fraction of the pan-genome is predicted to be involved in metabolic functions and hence these data are consistent with metabolic differentiation as a driver of population structure. However, this has so far remained unsubstantiated because in the past it was not possible to explore metabolic variation at scale. Here we used a combination of comparative genomics and high-throughput genome-scale metabolic modelling to systematically explore metabolic diversity across the K. pneumoniae species complex (n=7,835 genomes). We simulated growth outcomes for each isolate using carbon, nitrogen, phosphorus and sulfur sources under aerobic and anaerobic conditions (n=1,278 conditions per isolate). We showed that the distributions of metabolic genes and growth capabilities are structured in the population, and confirmed that sub-lineages exhibit unique metabolic profiles. In vitro co-culture experiments demonstrated reciprocal commensalistic cross-feeding between sub-lineages, effectively extending the range of conditions supporting individual growth. We propose that these substrate specialisations promote the existence and persistence of co-circulating sub-lineages by reducing nutrient competition and facilitating commensal interactions via negative frequency-dependent selection. Our findings have implications for understanding the eco-evolutionary dynamics of K. pneumoniae and for the design of novel strategies to prevent opportunistic infections caused by this World Health Organization priority antimicrobial resistant pathogen.