Antibiotic efficacy-context matters

Abstract

Antibiotic lethality is a complex physiological process, sensitive to external cues. Recent advances using systems approaches have revealed how events downstream of primary target inhibition actively participate in antibiotic death processes. In particular, altered metabolism, translational stress and DNA damage each contribute to antibiotic-induced cell death. Moreover, environmental factors such as oxygen availability, extracellular metabolites, population heterogeneity and multidrug contexts alter antibiotic efficacy by impacting bacterial metabolism and stress responses. Here we review recent studies on antibiotic efficacy and highlight insights gained on the involvement of cellular respiration, redox stress and altered metabolism in antibiotic lethality. We discuss the complexity found in natural environments and highlight knowledge gaps in antibiotic lethality that may be addressed using systems approaches.

Figure 1

Antibiotics induce active death processes underlying lethality. Target inhibition directly triggers lethality by disrupting essential cellular processes (black). Stress responses induced by such disruptions indirectly trigger lethality by increasing metabolic demand and generating metabolic byproducts that damage cellular components (e.g., DNA, proteins, lipids) (blue). Environmental factors tune antibiotic lethality by acting on stress responses and/or altering bacterial metabolism.

Figure 2

Environmental factors tune antibiotic lethality. Cues such as oxygen availability and extracellular metabolites impact cell death by acting on cell metabolism. Population heterogeneity and multidrug contexts protect against lethality by inducing stress responses and defense mechanisms.