Multidrug resistance in Klebsiella species in response to selective pressure and the extent to which it may be reversible is not yet fully understood. Since carbapenem-resistant Enterobacteriaceae (CRE) are considered as a public health threat by the World Health Organization (WHO) and the Centers for Disease Control and prevention (CDC), more studies need to be done to comprehend the evolution of their antibiotic resistance mechanisms to determine if it is possible to reverse this trend.
K. quasipneumoniae FK688 is a clinical isolate that was shown to be resistant to imipenem and have lost functional porin expression, one of the frequently occurring mechanisms of clinical multidrug resistance, such as inactivation of porin pump OmpK36 in K. pneumoniae. Since genome sequencing indicated that the ompK36 gene in FK688 was mutated, and potentially responsible for the increased resistance to imipenem, it is an interesting model to study the evolution process.
To study the evolution of imipenem resistance in FK688, the ompK36 gene in this strain is reverted to the wildtype “ompK+” genotype, where porin functionality is recovered, and therefore imipenem sensitivity is restored. The aim of this study is to compare the engineered imipenem-sensitive FK688 “ompK+” to the drug-resistant “ompK-” progenitor FK688 strain using evolution experiments a competitive fitness assay, where the fitness cost of the mutation at different times points will be monitored. Subsequently, whole genome sequence data will be used to evaluate the rates and occurrence of genetic changes occurring within the ompk36 gene along with other mutations, and how the “ompK+” strain evolves in the presence of antibiotic selection pressure
By identifying the evolutionary trajectory of the “ompK+” strain, this study will help us better understand how multidrug resistance potentially develops in clinical settings.