Our interests center on fundamental mechanisms that mediate bacterial growth in good times and bad, using E. coli as a model. Growth itself involves complex adjustments of global gene expression in response to nutrient availability and transitional shifts from one exhausted nutrient to another. Growth is also responsive to stress whether physical (heat, cold, pH, osmotic, radiation), chemical (antimetabolites, antibiotics, oxidants) or biological (viruses, toxins, host cell defenses and foreign DNA). Recent discoveries suggest emerging “nucleotide-centric” regulation across all biological kingdoms that involve monocyclic, dicyclic and heterodicyclic nucleotides as well as ppGpp and pppGpp. We continue study (p)ppGpp, which are two simple analogs of GDP and GTP. These mediate responses to nutritional and environmental stress in bacteria and plants with very weak suggestions of functions in animal cells.
Subtle changes in central metabolism are sensed, which lead to elevated (p)ppGpp and triggering adaptive responses. Only two of several sensing mechanisms are well studied. One senses anything causing a failure of charged tRNA availability to satisfy the demands of protein synthesis. The response is to activate a ribosomal (p)ppGpp synthetase. The other involves a different enzyme with a conformational switch between synthesis and hydrolysis sensed by binding of acylated acyl carrier protein (ACP). This system also responds with increased (p)ppGpp. Elevated (p)ppGpp leads to altered expression of about 1/3rd of the genome, limiting functions rendered unnecessary when growth slows and activating functions needed to adapt to the inciting stress. These seemingly esoteric fundamental findings turn out to be of substantial practical consequence. A transient metabolic dormancy due to high (p)ppGpp protects microbial pathogens from many host defenses, making them more pathogenic. Rare spontaneous spikes of ppGpp levels render pathogens resistant to otherwise susceptible antibiotics. When (p)ppGpp is totally absent, most pathogens are attenuated and carrier states are minimized.