The evolution of multidrug resistance in Klebsiella species in response to selective pressure and the extent to which this may be reversible is not fully understood. Since the spread of carbapenem-resistant Enterobacteriaceae (CRE) is considered a public health threat by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), more studies are needed to understand the evolution of antibiotic resistance mechanisms to determine if it is possible to reverse this trend.
A clinical Klebsiella quasipneumoniae isolate called FK688, which caused a bloodstream infection in a hospital patient, is resistant to multiple antibiotics, including third-generation cephalosporins and carbapenems. Analysis of the complete FK688 genome using short-read and long-read sequence data provided the first view of the gene synteny surrounding each of the outer-membrane porin genes in this species. Loss of functional porins is a mechanism by which bacterial cells can develop drug resistance due to reduced permeability of antibiotics into the cell. Genome sequencing showed that ompK35 has an insertion sequence in the promoter region and ompK36 contains a 48-bp deletion in the open-reading frame, resulting in the expression of a truncated non-functional outer membrane porin.
The genome data for FK688 also revealed the presence of a megaplasmid carrying a blaDHA-1 gene that encodes a plasmid-mediated class C-type (pAmpC) β-lactamase. A machine learning predictor, DeepBL, was used to confirm that FK688 does not encode any known carbapenemases. Gene conversion experiments were performed to demonstrate that it is the presence of blaDHA-1 together with non-functional porins that serve as a primary determinant of the CRE phenotype in K. quasipneumoniae FK688 and DHA-1 is contributing to a decreased susceptibility to carbapenems even in an OmpK36 expressing strain.