Multi-omics profiling reveals atypical sugar utilization and a key membrane composition regulator in Streptococcus pneumoniae

The human body comprises many different microenvironments, each with their own challenges for microorganisms to overcome in order to survive and possibly cause infection. The human pathogen Streptococcus pneumoniae is notoriously flexible in this regard, and can adapt to a wide range of host niches, including the nasopharynx, lungs, and cerebrospinal fluid. However, the molecular and genetic foundation of this ability remain largely uncharted. In this work, we demonstrate that niche adaptation imposes genome-wide changes on multiple levels, including gene essentiality, expression and membrane lipid composition, by using infection-mimicking growth conditions. In general, we show that gene expression and fitness profiling couple orthogonal sets of genes to environmental stimuli. For instance, import (manLMN) and catabolism (nagAB) genes are required, but not differentially expressed during growth on N-acetylglucosamine (GlcNAc), opposite to the pattern of other amino sugar metabolism pathways. Surprisingly, we find that pneumococci do not necessarily prefer glucose over GlcNAc and that uptake of GlcNAc in absence of subsequent catabolism is toxic. Moreover, we identify a previously overlooked fatty acid saturation regulator, FasR, controlling membrane composition, rendering it important during heat stress. As nutrient availability and temperature fluctuations are distinctive facets of infection environments, these findings may inform anti-infective strategies.