FIGURE 1.

(A). Antibiotic treatment increases metabolic stress (such as ROS) and leads to the activation of mutagenic stress-response pathways, resulting in de novo resistance mutations. The result is a higher number of antibiotic-resistant bacteria surviving antibiotic treatment (as shown on the antibiotic-containing media plates). To prevent these de novo resistance mutations and therefore limit resistance development, a compound can be administered to reduce the level of metabolic stress. Alternatively, mutagenesis can be reduced by inhibiting proteins important for activation of the mutagenic stress-response pathways. (B). Antibiotic treatment selects for members of the population harboring pre-existing resistance-conferring mutations or genes. These resistant bacteria can be targeted by a second antibiotic or by using a variety of adjuvants—non-antibiotics that can be combined with antibiotic therapy to limit resistance development. Such adjuvants include enzyme or efflux pump inhibitors as well as bacteriophages that selectively target bacteria resistant to the antibiotic.