Persistence and reversal of plasmid-mediated antibiotic resistance

Abstract

In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli. The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance.

Clinical extended-spectrum beta-lactamase antibiotic resistance plasmids have diverse transfer rates and can spread in the absence of antibiotic selection

“…Because all but one of our conjugative plasmids carry multiple replicons [44], which 386 is suggested to be a strategy to circumvent limitations to spread due to plasmid 387 incompatibility, we argue that the plasmid incompatibility in our conjugation assays to might 388 growth, we found that the increase in plasmid frequency was strongly correlated with plasmid 423 transfer rate (Fig 4). This might hold true even for costly plasmids, as others have shown that 424 transfer rates can surpass a fitness cost and allow plasmids to spread [26,47]. Foremost, we 425 found that all plasmids carrying the required tra genes spread from various donors through a 426 multitude of recipient populations.…”

“…In some cases, compensatory mutations have been shown to reduce plasmid cost in 111 the presence and absence of selective pressure [25]. In others, it is the high rates of 112 conjugation that allow a plasmid to persist despite a growth disadvantage [26]. With the 113 recent discovery of several novel defense systems against foreign DNA in bacteria [24], 114 interactions between bacteria, particularly during horizontal gene transfer, become 115 increasingly interesting to study.…”

“…The relative contributions of the various factors that drive plasmid spread remain poorly 119 understood, particularly for clinical plasmids [11]. Past studies have largely focused on types 120 of plasmids not directly relevant for resistance in clinical settings, or on individual plasmids 121 6 after moving them into model strains [22,[25][26][27] (notable exception [28]). Studies using 122 mouse models have contributed to our understanding of the processes that drive conjugation 123 within the gut, but these have mostly been limited to laboratory strains with conjugative 124 plasmids that are not clinically relevant [8,9,29,30].…”

Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations

“…From an experimental perspective, it is obvious that the specific in vitro conditions used here fail to capture numerous complexities associated with resistance in clinical settings (67), including substantial spatial heterogeneity, potential for biofilm formation, effects of the host immune system, and drug concentrations that differ in both magnitude and time-course from the specific scenarios considered here. In addition, our experimental model system is based on plasmid-mediated resistance, and while this fact is not explicitly assumed in any of our mathematical models, horizontal gene transfer may introduce new dynamics (68,69), particularly in high-density populations where conjugation is frequent. Nevertheless, the fact that population dynamics can be surprisingly complex, even under these simplified conditions, indicates that the spread of resistance alleles may not always follow simple selection dynamics.…”

Inhibiting conjugation as a tool in the fight against antibiotic resistance

“…COINS could also potentially be used as a pretreatment ahead of scheduled procedures that require antibiotic treatment to allow plasmid free cells to outcompete plasmid carriers since plasmids carry a fitness cost. At least in in vitro experiments this has been demonstrated (Getino et al, 2015;Lopatkin et al, 2017). In the livestock industry, all animals are typically treated if one or more animals fall sick because of the cost and difficulty to identify and treat only the sick (EMA, 2016).…”