Abstract
Collateral sensitivity (CS) is a promising alternative approach to counteract the rising problem of antibiotic resistance (ABR). CS occurs when the acquisition of resistance to one antibiotic produces increased susceptibility to a second antibiotic. Recent studies have focused on CS strategies designed against ABR mediated by chromosomal mutations. However, one of the main drivers of ABR in clinically relevant bacteria is the horizontal transfer of ABR genes mediated by plasmids. Here, we report the first analysis of CS associated with the acquisition of complete ABR plasmids, including the clinically important carbapenem-resistance conjugative plasmid pOXA-48. In addition, we describe the conservation of CS in clinical E. coli isolates and its application to selectively kill plasmid-carrying bacteria. Our results provide new insights that establish the basis for developing CS-informed treatment strategies to combat plasmid-mediated ABR.
Highlights
The rapid evolution of antibiotic resistance (ABR) in bacteria reduces the utility of clinically relevant antibiotics, making ABR one of the major challenges facing public health (Jim, 2016; MacLean and San Millan, 2019)
This led to the identification of seven Collateral sensitivity (CS) instances producing a consistent !2-fold reduction in antibiotic susceptibility, of which six showed significant reductions in antibiotic susceptibility
The disk-diffusion assays produced notably robust results with minimum hands-on time, suggesting that this technique is appropriate for screening CS responses in large strain collections. These results demonstrate that ABR plasmids produce moderate but significant CS to different antibiotics, comparable to that generated by ABR chromosomal mutations in E. coli (Imamovic and Sommer, 2013; Lazar et al, 2013; Podnecky et al, 2018)
Summary
The rapid evolution of antibiotic resistance (ABR) in bacteria reduces the utility of clinically relevant antibiotics, making ABR one of the major challenges facing public health (Jim, 2016; MacLean and San Millan, 2019). CS occurs when the acquisition of resistance to one antibiotic causes increased susceptibility to a second antibiotic (Szybalski and Bryson, 1952) and can be exploited for the design of multi-drug strategies that select against ABR (Imamovic and Sommer, 2013; Lazar et al, 2013). Several studies have cataloged CS networks emerging from mutations in chromosomal (Imamovic and Sommer, 2013; Lazar et al, 2013; Maltas and Wood, 2019; Podnecky et al, 2018; Roemhild et al, 2020) and plasmid genes (Dortet et al, 2015; Frohlich et al, 2019; Rosenkilde et al, 2019), but the CS effects produced by the horizontal acquisition of ABR plasmids remain poorly understood
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