Utilizing collateral effects of antibiotic resistance to sustain antibiotic efficacy and addressing current barriers to translation

Antimicrobial resistance (AMR) results from acquiring mutations or genes that allow microbes to withstand antimicrobials. These genetic modifications can also cause non-selected changes in other cell phenotypes, such as fitness and susceptibility to antibiotic classes different from the one under selection. These collateral effects of AMR acquisition could be exploited to improve treatments. This is increasingly important in light of AMR as a major global health problem, associated with 4.71 million deaths worldwide in 2021, with 1.14 million deaths directly attributable to AMR. Additionally, the lack of development of novel antimicrobials active against resistant infections continues to compound the crisis. Even if new antimicrobials are developed, resistance will most likely emerge through adaptive evolution. Therefore, it is imperative to explore strategies to maintain the efficacy of new and existing antibiotics and limit the acquisition of AMR to continue to treat infections successfully. Understanding the impact of resistance acquisition on the bacterial phenotype, including collateral effects, has the potential to improve therapeutic outcomes. In this perspective, we will summarize the collateral effects of resistance acquisition, including fitness costs, collateral susceptibility networks, mutant selection windows and the probability of establishment of bacterial populations, and explore how these may be exploited to enhance the effectiveness of existing antibiotics. We will also discuss how challenges such as genetic background, polymicrobial infections and the environment are current barriers to the translation of these principles into the clinic.