The effects of sub-lethal antibiotics on bacterial physiology

Abstract

Antibiotics are small molecules that kill bacteria by inhibiting essential processes. However, the concentrations used to kill bacteria in a clinical setting are typically much higher than the concentrations generated in nature, where most antibiotics are secreted by microbes. This discrepancy in concentrations, combined with a recognition that the human use of antibiotics bears little resemblance to the role of antibiotics in nature, prompted questions about whether growth inhibition was the primary function of antibiotics. Studying the effects of antibiotics at sub-lethal concentrations on bacteria could provide new insights into the natural role of antibiotics. One striking effect of bacterial encounters with sub-lethal antibiotics is the stimulation of biofilm formation. Biofilms are surface-adhered communities of bacteria. The biofilm lifestyle confers many benefits for bacteria and is a major mode of bacterial growth. Therefore, the ability of sub-lethal antibiotics to cause a transition from planktonic to biofilm growth indicates that antibiotics could be a driving force behind the assembly and abundance of bacterial communities in nature. Chapters Two and Three investigate the underlying mechanisms of this response in Escherichia coli and Pseudomonas aeruginosa, and suggest that sub-lethal antibiotics perturb central metabolism and respiration, changes that are sensed and relayed into increased biofilm formation to provide population-level protection. Chapters Four and Five investigate the effects of sub-lethal antibiotics on peptidoglycan metabolism in P. aeruginosa and E. coli. Peptidoglycan is an essential macromolecule for bacterial survival and is deeply integrated into their physiology. Furthermore, peptidoglycan synthesis is among the most favoured targets of antibiotics. Chapter Four investigates interactions between peptidoglycan-targeting antibiotics and folate metabolism-targeting antibiotics, and characterizes an overlooked connection between folate and peptidoglycan metabolism. Based on this work, we rationally designed a new inhibitor that potentiates folate and peptidoglycan-targeting antibiotics. Chapter Five sheds new light on peptidoglycan recycling by leveraging a pathway in P. aeruginosa for sensing and responding to sub-lethal doses of PG-targeting antibiotics. Finally, Chapter Six summarizes the understanding gained from Chapters Two through Five and synthesizes this information for broader insights on the possible roles of antibiotics in nature.