Antibiotic Lethality and Membrane Bioenergetics.

A growing body of research suggests bacterial metabolism and membrane bioenergetics affect the lethality of a broad spectrum of antibiotics. Electrochemical gradients spanning energy-transducing membranes are the foundation of the chemiosmotic hypothesis and are essential for life; accordingly, their dysfunction appears to be a critical factor in bacterial death. Proton flux across energy-transducing membranes is central for cellular homeostasis as vectorial proton translocation generates a proton motive force used for ATP synthesis, pH homeostasis, and maintenance of solute gradients. Our recent investigations indicate that maintenance of pH homeostasis is a critical factor in antibiotic killing and suggest an imbalance in proton flux initiates disruptions in chemiosmotic gradients that lead to cell death. The complex and interconnected relationships between electron transport systems, central carbon metabolism, oxidative stress generation, pH homeostasis, and electrochemical gradients provide challenging obstacles to deciphering the roles for each of these processes in antibiotic lethality. In this chapter, we will present evidence for the pH homeostasis hypothesis of antibiotic lethality that bactericidal activity flows from disruption of cellular energetics and loss of chemiosmotic homeostasis. A holistic understanding of the interconnection of energetic processes and antibiotic activity may direct future research toward the development of more effective therapeutic interventions.