Antiplasmid systems: a novel strategy to combat antibiotic resistance

Antibiotic resistance is a serious health threat of this century, responsible for millions of deaths annually due to the diminishing effect of currently used antibiotics. Bacteria become resistant through mutations or by the acquisition of genes conferring resistance. Determinants of resistance are often plasmids, which are small extrachromosomal DNA elements instrumental in disseminating antibiotic resistance genes (ARGs) through horizontal transfer (HGT). While plasmids may confer beneficial traits to bacteria, they also sometimes impose a fitness cost. To counter this, bacteria have evolved several defence mechanisms, such as prokaryotic Argonautes (pAgos), DNA defence module (DdmDE), ApsAB, Wadjet and Lamassu, which exhibit antiplasmid activity. The system restricts or degrades plasmid and phage DNA by various mechanisms, including abortive infection, replication interference or direct plasmid degradation. These antiplasmid systems offer the potential to specifically recognize and degrade the plasmid, rendering bacteria susceptible to antibiotics. This review highlights the in-depth understanding of these systems, including their structural diversity, from Argonaute-like proteins to SMC-based complexes, molecular mechanisms, origins and potential applications in combating plasmid-mediated antibiotic resistance. Furthermore, we have hypothesized two different ways of using the antiplasmid system to combat plasmid-borne drug resistance among bacterial pathogens.