Post-translational negative feedback loops are sufficient to coordinate synthesis of the gram-negative envelope during steady-state growth

How gram-negative bacteria coordinate the synthesis of their multilayered envelopes is a long-standing fundamental question. We compile protein and metabolite measurements obtained from Escherichia coli to eliminate mechanisms that do not coordinate envelope synthesis during steady-state growth. These measurements reveal that envelope synthesis pathway expression and envelope precursor concentrations are both stable across growth rates, thus eliminating enzyme levels and metabolite levels as coordination mechanisms. We propose instead that envelope assembly pathways are coordinated by post-translational mechanisms that control a small number of enzymes and transport proteins, which in turn control upstream synthesis pathways via classic negative feedback. We further hypothesize that many signals that have been proposed to directly regulate envelope synthesis pathways act indirectly via known negative feedback loops.