Frontiers in cellular and infection microbiology · 2026
The blaKPC-249 -mediated mechanism drives the transition of ST463 Pseudomonas aeruginosa from Ceftazidime-Avibactam sensitivity to resistance during clinical treatment.
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Li Xiaosi, Feng Yan, Wu Xiaoyan, Shen Heping, Shang Shumi, Tang Wenting, Hu Fupin, Liang Huijun
Аннотация
INTRODUCTION: Ceftazidime-avibactam represents a crucial therapeutic option for managing infections attributable to carbapenem-resistant P. aeruginosa. Nonetheless, the emergence of resistance to ceftazidime-avibactam in P. aeruginosa presents a significant challenge for clinical anti-infective therapy. This study primarily elucidates the mechanisms by which P. aeruginosa transitions from drug sensitivity to resistance during ceftazidime-avibactam treatment, ultimately resulting in therapeutic failure.
METHODS: The susceptibility testing was performed using the broth microdilution method, conjugation experiment was performed via the filter mating method, the genetic surroundings of bla KPC-249 and comparison of plasmids structures was performed using short/long-read genome sequencing and analysis method, the resistance of transconjugant carried the bla KPC-249 to ceftazidime-avibactam was performed via molecular cloning method.
RESULTS: For P. aeruginosa isolates from a patient, the minimum inhibitory concentrations (MICs) of ceftazidime-avibactam (CAZ-AVI) were determined as follows: isolates from sputum and bronchoalveolar lavage fluid both exhibited an MIC of 2 mg/L without blaKPC. In comparison, the blood-isolated strain P. aeruginosa PAE045 showed a significantly elevated MIC of >128 mg/L against CAZ-AVI. Plasmid conjugation experiments results demonstrated that the plasmid harboring the bla KPC-249 gene could be successfully transferred to the recipient strain PAO1 rifR (rifampicin-resistant P. aeruginosa PAO1). Third-generation sequencing results revealed that the bla KPC-249 gene was located on a plasmid with an approximate size of 37 kb. Compared with the wild-type e bla KPC-2 gene, the bla KPC-249 gene had two additional amino acid residues in its encoded protein: threonine (Thr, T) at position 182 and serine (Ser, S) at position 183. Furthermore, the upstream and downstream regions of the bla KPC-249 gene were flanked by the insertion sequences ISKpn6 and ISKpn27, respectively.
DISCUSSION: These mobile genetic elements may play a role in the capture and dissemination of the bla KPC-249 gene. The bla KPC-249 gene is identified as a novel mutant variant of the bla KPC gene family, which mediates the resistance of P. aeruginosa to the antimicrobial agent ceftazidime-avibactam.
METHODS: The susceptibility testing was performed using the broth microdilution method, conjugation experiment was performed via the filter mating method, the genetic surroundings of bla KPC-249 and comparison of plasmids structures was performed using short/long-read genome sequencing and analysis method, the resistance of transconjugant carried the bla KPC-249 to ceftazidime-avibactam was performed via molecular cloning method.
RESULTS: For P. aeruginosa isolates from a patient, the minimum inhibitory concentrations (MICs) of ceftazidime-avibactam (CAZ-AVI) were determined as follows: isolates from sputum and bronchoalveolar lavage fluid both exhibited an MIC of 2 mg/L without blaKPC. In comparison, the blood-isolated strain P. aeruginosa PAE045 showed a significantly elevated MIC of >128 mg/L against CAZ-AVI. Plasmid conjugation experiments results demonstrated that the plasmid harboring the bla KPC-249 gene could be successfully transferred to the recipient strain PAO1 rifR (rifampicin-resistant P. aeruginosa PAO1). Third-generation sequencing results revealed that the bla KPC-249 gene was located on a plasmid with an approximate size of 37 kb. Compared with the wild-type e bla KPC-2 gene, the bla KPC-249 gene had two additional amino acid residues in its encoded protein: threonine (Thr, T) at position 182 and serine (Ser, S) at position 183. Furthermore, the upstream and downstream regions of the bla KPC-249 gene were flanked by the insertion sequences ISKpn6 and ISKpn27, respectively.
DISCUSSION: These mobile genetic elements may play a role in the capture and dissemination of the bla KPC-249 gene. The bla KPC-249 gene is identified as a novel mutant variant of the bla KPC gene family, which mediates the resistance of P. aeruginosa to the antimicrobial agent ceftazidime-avibactam.