The plasmid-mediated spread of multi-drug resistance (MDR) to human pathogens is threatening our fight against infectious diseases. Hence, we need novel therapies aimed at limiting the spread of new resistance genes. However, while we and others have shown that the long-term persistence of a plasmid can improve in a bacterial host either by mutations in the plasmid, the host or both (De Gelder et al., 2008; Sota et al., 2010; Hughes et al., 2012; Stalder et al., 2017), only in very few cases have the molecular mechanisms been unraveled (Loftie-Eaton et al., 2016; Yano et al., 2016). We have also shown that evolutionary pattenrs in bacterial biofilms differ from those in well-mixed liquid cultures (Ridenhour et al., 2017)
For the molecular mechanisms to become useful targets for alternative therapies to slow down the spread of resistance, they should be common among multiple pathogen. We and others have identified critical mutations in chromosomally encoded accessory helicases (Loftie-Eaton et al., 2017). Plasmid-helicase interactions in bacteria may thus be key to the ability of bacterial pathogens to retain newly acquired MDR plasmids. We also showed for the first time that these mutations pre-adapt the bacteria to other MDR plasmids that they acquire later in time, leading to enhanced retention of mobile resistance genes (designated ‘increased plasmid permissiveness’; Loftie-Eaton et al., 2017). Bacteria with increased permissiveness can thus serve as stable repositories for multiple MDR plasmids, eventually generating strains with an expanded arsenal of resistance genes. Using molecular techniques, experimental evolution and mathematical modeling, we are now testing the following hypotheses: (i) chromosomal mutations can pre-adapt bacteria to other plasmids, leading to greater plasmid permissiveness; (ii) plasmid permissiveness can expand the spectrum of antibiotic resistance traits within a bacterial species; and (iii) accessory helicases are linked to the persistence of newly acquired MDR plasmids across a wide spectrum of bacterial pathogens.