Abstract:
During infection, bacterial pathogens face significant challenges due to host-imposed
nutritional immunity, particularly iron limitation. Staphylococcus lugdunensis, a known
opportunistic pathogen, has evolved to overcome this restriction by utilizing host-
derived heme as an iron source, facilitated by the SLUSH locus. This locus encodes
SLUSH peptides that exhibit hemolytic activity, enabling the pathogen to lyse
erythrocytes and release heme. Our study reveals that the SLUSH peptides play a
critical role in iron acquisition and contribute significantly to S. lugdunensis virulence,
particularly under iron-restricted conditions. We show that the SLUSH peptides are
essential for erythrocyte-dependent growth of S. lugdunensis in vitro, confirming their
role in heme acquisition. Additionally, Agr (accessory gene regulator), a key regulator
of PSM expression in Staphylococcus aureus, also regulates the SLUSH locus in
S. lugdunensis, underscoring its importance in overcoming host defenses.
In the context of cystic fibrosis (CF), Pseudomonas aeruginosa and S. aureus
frequently co-colonize the lungs, leading to complex metabolic interactions. Genome-
scale metabolic models (GEMs) are widely used to predict microbial interactions, but
their accuracy is often limited in complex environments when transcriptional data are
excluded. In this study, we integrated transcriptomic data to refine GEMs for
P. aeruginosa and S. aureus under cystic fibrosis (CF)-like conditions. While co-
culturing these species revealed significant metabolic changes, particularly in amino
acid biosynthesis and fermentation, the refined models still failed to capture the
dynamic metabolic shifts driven by interspecies competition fully. Notably, we
observed downregulation of the pvdE gene in P. aeruginosa, involved in iron
acquisition, suggesting that S. aureus modulates P. aeruginosa iron metabolism.
These findings highlight key limitations of current GEMs, particularly their inability to
account for complex interspecies interactions such as siderophore utilization and
regulatory network dynamics. Overall, our study provides new insights in
S. lugdunensis hemolytic activity and microbial interactions in CF lungs, underscoring
2
Abstract
the need for further refinement of GEMs by incorporating regulatory and interspecies
signalling mechanisms.
