Antibiotic tolerance enables bacteria to survive bactericidal antibiotic exposure and has been linked to resistance evolution in laboratory systems and individual infections, but its role in plasmid-mediated resistance evolution in clinical populations remains unclear. Here, we analyzed a longitudinal collection of more than 800 clinical Klebsiella pneumoniae isolates spanning 1997-2020. Among 779 minimum inhibitory concentration (MIC)-defined ertapenem-susceptible isolates, 137 (17.6%) displayed hidden ertapenem tolerance, defined by enhanced survival after 6 h at 30 times the isolate-specific ertapenem MIC, mostly without extended lag time or reduced growth rate. Tolerance was detected before local ertapenem introduction and was enriched among ertapenem-resistant isolates, supporting a population-level association between pre-existing tolerance and the emergence of carbapenem resistance. Genomic and plasmid-curing analyses separated plasmid-mediated carbapenem resistance from plasmid-independent antibiotic tolerance. Moreover, tolerant recipient backgrounds enhanced resistance plasmid acquisition, preserved viable recipients following antibiotic exposure and accelerated ceftazidime-avibactam resistance evolution. A phylogeny-guided variant-enrichment analysis further identified the uhpABC regulatory operon as a candidate tolerance-associated locus, and coordinated expression of the complete operon increased ertapenem survival. Together, these findings identify clinical antibiotic tolerance as a pre-existing, MIC-hidden phenotype that can facilitate plasmid-mediated carbapenem resistance evolution in K. pneumoniae.
zhang, W., Zheng, B., Zhou, M., Zhang, R., Xu, Y., Liu, J.
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