Stepwise evolution of pandrug-resistance in Klebsiella pneumoniae

Abstract

Carbapenem resistant Enterobacteriaceae (CRE) pose an urgent risk to global human health. CRE that are non-susceptible to all commercially available antibiotics threaten to return us to the pre-antibiotic era. Using Single Molecule Real Time (SMRT) sequencing we determined the complete genome of a pandrug-resistant Klebsiella pneumoniae isolate, representing the first complete genome sequence of CRE resistant to all commercially available antibiotics. The precise location of acquired antibiotic resistance elements, including mobile elements carrying genes for the OXA-181 carbapenemase, were defined. Intriguingly, we identified three chromosomal copies of an ISEcp1-blaOXA-181 mobile element, one of which has disrupted the mgrB regulatory gene, accounting for resistance to colistin. Our findings provide the first description of pandrug-resistant CRE at the genomic level, and reveal the critical role of mobile resistance elements in accelerating the emergence of resistance to other last resort antibiotics.

Emergence and Evolution of Multidrug-Resistant Klebsiella pneumoniae with both bla KPC and bla CTX-M Integrated in the Chromosome

“…2C) (15), KPNIH33 carries two chromosomal bla KPC-3 copies with Tn4401b (14,15), and MS6671 carries three chromosomal bla OXA-181 copies with ISEcp1 (Fig. 1B) (22). We describe that the CN1 chromosome carries three bla CTX-M-15 copies with ISEcp1 and one bla KPC-2 copy with Tn4401a.…”

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

“…Insertional inactivation caused by diverse insertion sequences (IS), belonging to several families and inserted at different locations within the mgrB gene, is often responsible for acquired resistance to colistin in K. pneumoniae (105,117,120,(130)(131)(132) and Klebsiella oxytoca (133,134). Recently, the transposition of genes encoding extended-spectrum ␤-lactamases (ESBLs) or carbapenemases, leading to disruption of the chromosomal mgrB gene, was reported as a source of resistance to colistin (135,136). Notably, selective pressure with ␤-lactams leading to the acquisition of ␤-lactamase genes may therefore be responsible for coselection of colistin resistance.…”

Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae Mediated by Chromosomal Integration of Plasmid DNA

“…Similarly, it has been suggested ISKpn25 is involved in DNA rearrangements among pKpQIL-like and possibly other plasmids (11). An additional study showed that a mobile element containing the carbapenemase OXA-181 disrupted the mgrB gene in a carbapenem-and colistin-resistant K. pneumoniae isolate from a patient from the United Arab Emirates (12). In the same isolate, a copy of a second element harboring CTX-M-15 (ISEcp1-bla CTX-M-15 ) was inserted into ompK35, inactivating the gene.…”