Systems analysis of microbial adaptations to simultaneous stresses.

Microbes live in multi-factorial environments and have evolved under a variety of concurrent stresses including resource scarcity. Their metabolic organization is a reflection of their evolutionary histories and, in spite of decades of research, there is still a need for improved theoretical tools to explain fundamental aspects of microbial physiology. Using ecological and economic concepts, this chapter explores a resource-ratio based theory to elucidate microbial strategies for extracting and channeling mass and energy. The theory assumes cellular fitness is maximized by allocating scarce resources in appropriate proportions to multiple stress responses. Presented case studies deconstruct metabolic networks into a complete set of minimal biochemical pathways known as elementary flux modes. An economic analysis of the elementary flux modes tabulates enzyme atomic synthesis requirements from amino acid sequences and pathway operating costs from catabolic efficiencies, permitting characterization of inherent tradeoffs between resource investment and phenotype. A set of elementary flux modes with competitive tradeoffs properties can be mathematically projected onto experimental fluxomics datasets to decompose measured phenotypes into metabolic adaptations, interpreted as cellular responses proportional to the experienced culturing stresses. The resource-ratio based method describes the experimental phenotypes with greater accuracy than other contemporary approaches and further analysis suggests the results are both statistically and biologically significant. The insight into metabolic network design principles including tradeoffs associated with concurrent stress adaptation provides a foundation for interpreting physiology as well as for rational control and engineering of medically, environmentally, and industrially relevant microbes.