TY - JOUR TI - Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics AU - Ma, Peijun AU - He, Lorrie L AU - Pironti, Alejandro AU - Laibinis, Hannah H AU - Ernst, Christoph M AU - Manson, Abigail L AU - Bhattacharyya, Roby P AU - Earl, Ashlee M AU - Livny, Jonathan AU - Hung, Deborah T A2 - Rokas, Antonis A2 - Perry, George H A2 - Barbosa, Camilo VL - 10 PY - 2021 DA - 2021/04/19 SP - e67310 C1 - eLife 2021;10:e67310 DO - 10.7554/eLife.67310 UR - https://doi.org/10.7554/eLife.67310 AB - In this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of ‘last resort’, in Klebsiella pneumoniae, the major carbapenem-resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant lineages. A broader spectrum of resistance-conferring mutations for select carbapenems such as ertapenem also enables higher resistance frequencies and, importantly, creates stepping-stones to achieve high-level resistance to all carbapenems. These mutational mechanisms can contribute to the evolution of resistance, in conjunction with the loss of systems that restrict horizontal resistance gene uptake, such as the CRISPR-Cas system. Given the need for greater antibiotic stewardship, these findings argue that in addition to considering the current efficacy of an antibiotic for a clinical isolate in antibiotic selection, considerations of future efficacy are also important. The genetic background of a clinical isolate and the exact antibiotic identity can and should also be considered as they are determinants of a strain's propensity to become resistant. Together, these findings thus provide a molecular framework for understanding acquisition of carbapenem resistance in K. pneumoniae with important implications for diagnosing and treating this important class of pathogens. KW - antibiotics KW - resistance KW - evolution KW - klebsiella KW - carbapenem JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -