Multiple Novel Ceftazidime-Avibactam-Resistant Variants of
            <i>bla</i>
            <sub>KPC-2</sub>
            -Positive Klebsiella pneumoniae in Two Patients

Shi, Qingyu; Han, Renru; Guo, Yan; Yang, Yang; Shi, Wei; Zhang, Rong; Yin, Daqiang; Hu, Fupin

doi:10.1128/spectrum.01714-21

Cited by 10 publications

(3 citation statements)

References 49 publications

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“…The Nucleotide BLAST (BLASTn) search found that plasmid B had the highest alignment score in the whole sequence with the previously reported plasmid pB (CP069172.1) 33 with query coverage and identity of 96% and 99.98%, respectively, and with pZHKPC1 (OM928502.1) 34 with query coverage and identity of 95% and 100% respectively.…”

Section: Resultsmentioning

confidence: 55%

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Phenotypic and Genetic Analysis of KPC-49, a KPC-2 Variant Conferring Resistance to Ceftazidime–Avibactam and Maintaining Resistance to Imipenem and Meropenem

Meng¹,

Wei²,

Song³

et al. 2023

IDR

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Klebsiella pneumoniae, a gram-negative bacterium, poses a severe hazard to public health, with many bacterial hosts having developed resistance to most antibiotics in clinical use. The goal of this study was to look into the development of resistance to both ceftazidime-avibactam and carbapenems, including imipenem and meropenem, in a K. pneumonia strain expressing a novel K. pneumoniae carbapenemase-2 (KPC-2) variant, referred to as KPC-49. Methods: After 1 day of incubation of K1 on agar containing ceftazidime-avibactam (MIC = 16/4 mg/L), a second KPC-producing K. pneumoniae strain (K2) was recovered. Antimicrobial susceptibility assays, cloning assays, and whole genome sequencing were performed to analyse and evaluate antibiotic resistance phenotypes and genotypes. Results: K. pneumoniae strain (K1), that produced KPC-2, was susceptible to ceftazidime-avibactam but resistant to carbapenems. The K2 isolate harboured a novel bla KPC-49 variant, which differs from bla KPC-2 by a single nucleotide (C487A), and results in an arginine-serine substitution at amino acid position 163 (R163S). The mutant K2 strain was resistant to both ceftazidime-avibactam and carbapenems. We demonstrated the ability of KPC-49 to hydrolyse carbapenems, which may be attributed to high KPC-49 expression or presence of an efflux pump and/or absence of membrane pore proteins in K2. Furthermore, bla KPC-like was carried on an IncFII (pHN7A8)/IncR-type plasmid within a TnAs1-orf-orf-orf-orf-orf-orf-ISKpn6-bla KPC -ISKpn27 structure. The bla KPC-like gene was flanked by various insertion sequences and transposon elements, including the Tn3 family transposon, such as TnAs1, TnAs3, IS26, and IS481-ISKpn27. Conclusion: New KPC variants are emerging owing to sustained exposure to antimicrobials and modifications in their amino acid sequences. We demonstrated the drug resistance mechanisms of the new mutant strains through experimental whole genome sequencing combined with bioinformatics analysis. Enhanced understanding of laboratory and clinical features of infections due to K. pneumoniae of the new KPC subtype is key to early and accurate anti-infective therapy.

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Section: Resultsmentioning

confidence: 55%

“…Our analysis revealed that the KPC-49 variant was carried on an IncFII/IncR type bla KPC -bearing plasmid. IncFII/IncR type plasmids are frequently isolated from K. pneumoniae , including the pZHKPC1, 34 pHS2953-KPC, and p12085-KPC plasmids, as well as from other gram-negative bacteria, including the p16055-KPC plasmid from S. marcescens .…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Genetic Analysis of KPC-49, a KPC-2 Variant Conferring Resistance to Ceftazidime–Avibactam and Maintaining Resistance to Imipenem and Meropenem

Meng¹,

Wei²,

Song³

et al. 2023

IDR

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“…Worryingly, several hospitals across Europe and China have now reported the emergence of ceftazidime/avibactam-resistant K. pneumoniae isolates, including KPC-2 and KPC-3-producing strains. − This concerning trend highlights the importance of developing our understanding of the precise mechanism(s) of action of ceftazidime/avibactam at the molecular level. Most, if not all, antibiotics have multiple targets or at least multiple effects, i.e., more than one mechanism of action, motivating the thorough exploration of multitarget approaches to combat resistant bacteria .…”

mentioning

confidence: 99%

Integrated Transcriptomic and Metabolomic Mapping Reveals the Mechanism of Action of Ceftazidime/Avibactam against Pan-Drug-Resistant Klebsiella pneumoniae

Hussein,

Allobawi,

Zhao

et al. 2023

ACS Infect. Dis.

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Here, we employed an integrated metabolomics and transcriptomics approach to investigate the molecular mechanism(s) of action of ceftazidime/avibactam against a pan-drugresistant K. pneumoniae clinical isolate from a patient with urinary tract infection. Ceftazidime/avibactam induced time-dependent perturbations in the metabolome and transcriptome of the bacterium, mainly at 6 h, with minimal effects at 1 and 3 h. Metabolomics analysis revealed a notable reduction in essential lipids involved in outer membrane glycerolipid biogenesis. This disruption effect extended to peptidoglycan and lipopolysaccharide biosynthetic pathways, including lipid A and O-antigen assembly. Importantly, ceftazidime/avibactam not only affected the final steps of peptidoglycan biosynthesis in the periplasm, a common mechanism of ceftazidime action, but also influenced the synthesis of lipid-linked intermediates and early stages of cytoplasmic peptidoglycan synthesis. Furthermore, ceftazidime/avibactam substantially inhibited central carbon metabolism (e.g., the pentose phosphate pathway and tricarboxylic acid cycle). Consistently, the dysregulation of genes governing these metabolic pathways aligned with the metabolomics findings. Certain metabolomics and transcriptomics signatures associated with ceftazidime resistance were also perturbed. Consistent with the primary target of antibiotic activity, biochemical assays also confirmed the direct impact of ceftazidime/avibactam on peptidoglycan production. This study explored the intricate interactions of ceftazidime and avibactam within bacterial cells, including their impact on cell envelope biogenesis and central carbon metabolism. Our findings revealed the complexities of how ceftazidime/avibactam operates, such as hindering peptidoglycan formation in different cellular compartments. In summary, this study confirms the existing hypotheses about the antibacterial and resistance mechanisms of ceftazidime/avibactam while uncovering novel insights, including its impact on lipopolysaccharide formation.

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Avibactam/ceftazidime/meropenem

2022

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Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients

Cited by 10 publications

References 49 publications

Phenotypic and Genetic Analysis of KPC-49, a KPC-2 Variant Conferring Resistance to Ceftazidime–Avibactam and Maintaining Resistance to Imipenem and Meropenem

Phenotypic and Genetic Analysis of KPC-49, a KPC-2 Variant Conferring Resistance to Ceftazidime–Avibactam and Maintaining Resistance to Imipenem and Meropenem

Integrated Transcriptomic and Metabolomic Mapping Reveals the Mechanism of Action of Ceftazidime/Avibactam against Pan-Drug-Resistant Klebsiella pneumoniae

Avibactam/ceftazidime/meropenem

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Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla KPC-2 -Positive Klebsiella pneumoniae in Two Patients

Cited by 10 publications

References 49 publications

Phenotypic and Genetic Analysis of KPC-49, a KPC-2 Variant Conferring Resistance to Ceftazidime–Avibactam and Maintaining Resistance to Imipenem and Meropenem

Phenotypic and Genetic Analysis of KPC-49, a KPC-2 Variant Conferring Resistance to Ceftazidime–Avibactam and Maintaining Resistance to Imipenem and Meropenem

Integrated Transcriptomic and Metabolomic Mapping Reveals the Mechanism of Action of Ceftazidime/Avibactam against Pan-Drug-Resistant Klebsiella pneumoniae

Avibactam/ceftazidime/meropenem

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Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla _KPC-2 -Positive Klebsiella pneumoniae in Two Patients