Antimicrobial resistance in the wild: Insights from epigenetics

Spreading of bacterial and fungal strains that are resistant to antimicrobials poses a serious threat to the well-being of humans, animals, and plants. Antimicrobial resistance has been mainly investigated in clinical settings. However, throughout their evolutionary history microorganisms in the wild have encountered antimicrobial substances, forcing them to evolve strategies to combat antimicrobial action. It is well known that many of these strategies are based on genetic mechanisms, but these do not fully explain important aspects of the antimicrobial response such as the rapid development of resistance, reversible phenotypes, and hetero-resistance. Consequently, attention has turned toward epigenetic pathways that may offer additional insights into antimicrobial mechanisms. The aim of this review is to explore the epigenetic mechanisms that confer antimicrobial resistance, focusing on those that might be relevant for resistance in the wild. First, we examine the presence of antimicrobials in natural settings. Then we describe the documented epigenetic mechanisms in bacteria and fungi associated with antimicrobial resistance and discuss innovative epigenetic editing techniques to establish causality in this context. Finally, we discuss the relevance of these epigenetic mechanisms on the evolutionary dynamics of antimicrobial resistance in the wild, emphasizing the critical role of priming in the adaptation process. We underscore the necessity of incorporating non-genetic mechanisms into our understanding of antimicrobial resistance evolution. These mechanisms offer invaluable insights into the dynamics of antimicrobial adaptation within natural ecosystems.