Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae
Ceftazidime-avibactam resistance attributable to the blaKPC-2 gene mutation is increasingly documented in clinical settings. In this study, we characterized the mechanisms leading to the development of ceftazidime-avibactam resistance in ST11-K47 hypervirulent Klebsiella pneumoniae that harboured th...
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Taylor & Francis Group
2024-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2024.2361007 |
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| author | Qingyu Shi Siquan Shen Chengkang Tang Li Ding Yan Guo Yang Yang Shi Wu Renru Han Dandan Yin Fupin Hu |
| author_facet | Qingyu Shi Siquan Shen Chengkang Tang Li Ding Yan Guo Yang Yang Shi Wu Renru Han Dandan Yin Fupin Hu |
| author_sort | Qingyu Shi |
| collection | DOAJ |
| description | Ceftazidime-avibactam resistance attributable to the blaKPC-2 gene mutation is increasingly documented in clinical settings. In this study, we characterized the mechanisms leading to the development of ceftazidime-avibactam resistance in ST11-K47 hypervirulent Klebsiella pneumoniae that harboured the blaKPC-135 gene. This strain possessed fimbriae and biofilm, demonstrating pathogenicity. Compared with the wild-type KPC-2 carbapenemase, the novel KPC-135 enzyme exhibited a deletion of Glu168 and Leu169 and a 15-amino acid tandem repeat between Val262 and Ala276. The blaKPC-135 gene was located within the Tn6296 transposon truncated by IS26 and carried on an IncFII/IncR-type plasmid. Compared to the blaKPC-2-positive cloned strain, only the MIC of ceftazidime increased against blaKPC-135-positive K. pneumoniae and wasn’t inhibited by avibactam (MIC 32 μg/mL), while clavulanic acid and vaborbactam demonstrated some inhibition. Kinetic parameters revealed that KPC-135 exhibited a lower Km and kcat/Km with ceftazidime and carbapenems, and a higher (∼26-fold) 50% inhibitory concentration with avibactam compared to KPC-2. The KPC-135 enzyme exerted a detrimental effect on fitness relative to the wild-type strain. Furthermore, this strain possessed hypervirulent determinants, which included the IncHI1B/FIB plasmid with rmpA2 and expression of type 1 and 3 fimbriae. In conclusion, we reported a novel KPC variant, KPC-135, in a clinical ST11-K47 hypervirulent K. pneumoniae strain, which conferred ceftazidime-avibactam resistance, possibly through increased ceftazidime affinity and decreased avibactam susceptibility. This strain simultaneously harboured resistance and virulence genes, posing an elevated challenge in clinical treatment. |
| format | Article |
| id | doaj-art-6912819c762c49e2959da541d64b54e7 |
| institution | Kabale University |
| issn | 2222-1751 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | Emerging Microbes and Infections |
| spelling | doaj-art-6912819c762c49e2959da541d64b54e72024-12-07T04:40:17ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512024-12-0113110.1080/22221751.2024.2361007Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniaeQingyu Shi0Siquan Shen1Chengkang Tang2Li Ding3Yan Guo4Yang Yang5Shi Wu6Renru Han7Dandan Yin8Fupin Hu9Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCeftazidime-avibactam resistance attributable to the blaKPC-2 gene mutation is increasingly documented in clinical settings. In this study, we characterized the mechanisms leading to the development of ceftazidime-avibactam resistance in ST11-K47 hypervirulent Klebsiella pneumoniae that harboured the blaKPC-135 gene. This strain possessed fimbriae and biofilm, demonstrating pathogenicity. Compared with the wild-type KPC-2 carbapenemase, the novel KPC-135 enzyme exhibited a deletion of Glu168 and Leu169 and a 15-amino acid tandem repeat between Val262 and Ala276. The blaKPC-135 gene was located within the Tn6296 transposon truncated by IS26 and carried on an IncFII/IncR-type plasmid. Compared to the blaKPC-2-positive cloned strain, only the MIC of ceftazidime increased against blaKPC-135-positive K. pneumoniae and wasn’t inhibited by avibactam (MIC 32 μg/mL), while clavulanic acid and vaborbactam demonstrated some inhibition. Kinetic parameters revealed that KPC-135 exhibited a lower Km and kcat/Km with ceftazidime and carbapenems, and a higher (∼26-fold) 50% inhibitory concentration with avibactam compared to KPC-2. The KPC-135 enzyme exerted a detrimental effect on fitness relative to the wild-type strain. Furthermore, this strain possessed hypervirulent determinants, which included the IncHI1B/FIB plasmid with rmpA2 and expression of type 1 and 3 fimbriae. In conclusion, we reported a novel KPC variant, KPC-135, in a clinical ST11-K47 hypervirulent K. pneumoniae strain, which conferred ceftazidime-avibactam resistance, possibly through increased ceftazidime affinity and decreased avibactam susceptibility. This strain simultaneously harboured resistance and virulence genes, posing an elevated challenge in clinical treatment.https://www.tandfonline.com/doi/10.1080/22221751.2024.2361007Carbapenem-resistant Klebsiella pneumoniaST11-K47hypervirulentceftazidime-avibactamblaKPC-135blaKPC-2 |
| spellingShingle | Qingyu Shi Siquan Shen Chengkang Tang Li Ding Yan Guo Yang Yang Shi Wu Renru Han Dandan Yin Fupin Hu Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae Emerging Microbes and Infections Carbapenem-resistant Klebsiella pneumonia ST11-K47 hypervirulent ceftazidime-avibactam blaKPC-135 blaKPC-2 |
| title | Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae |
| title_full | Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae |
| title_fullStr | Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae |
| title_full_unstemmed | Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae |
| title_short | Molecular mechanisms responsible KPC-135-mediated resistance to ceftazidime-avibactam in ST11-K47 hypervirulent Klebsiella pneumoniae |
| title_sort | molecular mechanisms responsible kpc 135 mediated resistance to ceftazidime avibactam in st11 k47 hypervirulent klebsiella pneumoniae |
| topic | Carbapenem-resistant Klebsiella pneumonia ST11-K47 hypervirulent ceftazidime-avibactam blaKPC-135 blaKPC-2 |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2024.2361007 |
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