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KPC-2-Producing Carbapenem-Resistant Klebsiella pneumoniae of the Uncommon ST29 Type Carrying OXA-926, a Novel Narrow-Spectrum OXA β-Lactamase.

ABSTRACT: We isolated and characterized a carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical strain from blood carrying a novel bla _OXA gene, bla _OXA-926, and belonging to ST29, an uncommon CRKP type. The strain, 130002, was genome sequenced using both short- and long-read sequencing and has a 94.9-kb self-transmissible IncFII plasmid carrying bla _KPC-2. K. pneumoniae genomes of the ST29 complex (ST29 and its single-allele variants) were retrieved and were subjected to single nucleotide polymorphism-based phylogenomic analysis. A total of 157 genomes of the ST29 complex were identified. This complex is commonly associated with extended-spectrum β-lactamase-encoding genes, in particular, bla _CTX-M-15 but rarely has carbapenemase genes. The novel plasmid-encoded β-lactamase-encoding gene bla _OXA-926 was identified on a 117.8-kb IncFIA-IncFII plasmid, which was transferrable in the presence of the bla _KPC-2-carrying plasmid. bla _OXA-926 was cloned and MICs of β-lactams in the transformants were determined using microdilution. OXA-926 has a narrow spectrum conferring reduced susceptibility only to piperacillin, piperacillin-tazobactam, and cephalothin. Avibactam cannot fully inhibit OXA-926. bla _OXA-926 and its variants have been seen in Klebsiella strains in Asia and Brazil. OXA-926 is the closest in sequence identity (89.9%) to a chromosome-encoding OXA-type enzyme of Variovorax guangxiensis. In conclusion, OXA-926 is novel plasmid-borne narrow-spectrum β-lactamase that cannot be fully inhibited by avibactam. It is likely that bla _OXA-926 originates from a species closely related to V. guangxiensis and was introduced into Klebsiella > 10 years ago.

SUBMITTER: Liu L

PROVIDER: S-EPMC8430219 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Carbapenem-resistant Enterobacteriaceae (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged diazabicyclooctane (DBO) β-lactamase inhibitor that inactivates class A and C β-lactamases and exhibits intrinsic antibiotic and β-lactam "enhancer" activity against Enterobacteriaceae In this study, we examined a collection of meropenem-resistant K. pneumoniae isolates carrying blaKPC-2 or blaKPC-3; meropenem-nacubactam restored susceptibility. Upon testing isogenic Escherichia coli strains producing KPC-2 variants with single-residue substitutions at important Ambler class A positions (K73, S130, R164, E166, N170, D179, K234, E276, etc.), the K234R variant increased the meropenem-nacubactam MIC compared to that for the strain producing KPC-2, without increasing the meropenem MIC. Correspondingly, nacubactam inhibited KPC-2 (apparent Ki [Ki app] = 31 ± 3 μM) more efficiently than the K234R variant (Ki app = 270 ± 27 μM) and displayed a faster acylation rate (k2/K), which was 5,815 ± 582 M-1 s-1 for KPC-2 versus 247 ± 25 M-1 s-1 for the K234R variant. Unlike avibactam, timed mass spectrometry revealed an intact sulfate on nacubactam and a novel peak (+337 Da) with the K234R variant. Molecular modeling of the K234R variant showed significant catalytic residue (i.e., S70, K73, and S130) rearrangements that likely interfere with nacubactam binding and acylation. Nacubactam's aminoethoxy tail formed unproductive interactions with the K234R variant's active site. Molecular modeling and docking observations were consistent with the results of biochemical analyses. Overall, the meropenem-nacubactam combination is effective against carbapenem-resistant K. pneumoniae Moreover, our data suggest that β-lactamase inhibition by nacubactam proceeds through an alternative mechanism compared to that for avibactam.

Dataset Information

KPC-2-Producing Carbapenem-Resistant Klebsiella pneumoniae of the Uncommon ST29 Type Carrying OXA-926, a Novel Narrow-Spectrum OXA β-Lactamase.

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