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Amina Nazir,1,2,* Yachao Zhao,2,* Manli Li,2 Rakia Manzoor,3,4 Rana Adnan Tahir,1 Xianglilan Zhang,2 Hong Qing,1 Yigang Tong2 1Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Sciences, Beijing Institute of Technology, Beijing, People’s Republic of China; 2State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People’s Republic of China; 3State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China; 4School of Life Science, University of Chinese Academy of Sciences, Beijing 100101, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong QingKey Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Sciences, Beijing Institute of Technology, Beijing, People’s Republic of ChinaTel +8613264286266Email hqing@bit.edu.cnYigang TongState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People’s Republic of ChinaEmail tong.yigang@gmail.comBackground: Multidrug-resistant plasmids carrying replication genes have been widely present in various strains of Klebsiella pneumoniae. RepA and repB1 were found in plasmids belong to the IncFIB, but their detailed structural and genomic characterization was not reported yet. This is the first study that delivers structural and functional insights of repA- and repB1-carrying IncFIB plasmids.Methods: Klebsiella pneumoniae strains A1705, 911021, and 1642 were isolated from the human urine samples and bronchoalveolar fluids collected from different hospitals of China. Antibacterial susceptibility and plasmid transfer ability were tested to characterize the resistant phenotypes mediated by the pA1705-qnrS, p911021-tetA, and p1642-tetA. The complete nucleotide sequences of these plasmids were determined through high-throughput sequencing technology and comparative genomic analyses of plasmids belong to the same incompatibility group were executed to extract the genomic variations and features.Results: The pA1705-qnrS, p911021-tetA, and p1642-tetA are defined as non-conjugative plasmids, having two replication genes, repA and repB1 associated with IncFIB family, and unknown incompatible group, respectively. Comparative genomic analysis revealed that relatively small backbones of IncFIB plasmids integrated massive accessory module at one “hotspot” that was located between orf312 and repB1. These IncFIB plasmids exhibited the distinct profiles of accessory modules including one or two multidrug-resistant regions, many complete and remnant mobile elements comprising integrons, transposons and insertion sequences. The clusters of resistant genes were recognized in this study against different classes of antibiotics including β-lactam, phenicol, aminoglycoside, tetracycline, quinolone, trimethoprim, sulfonamide, tunicamycin, and macrolide. It has been observed that all resistant genes were located in multidrug resistance regions.Conclusion: It is concluded that multidrug-resistant repA and repB1-carrying IncFIB plasmids are a key source to mediate the resistance through mobile elements among Klebsiella pneumoniae. Current findings provide a deep understanding of horizontal gene transfer among plasmids of the IncFIB family via mobile elements that will be utilized in further in vitro studies.Keywords: plasmids, repA, repB1, multidrug resistance, structural genomics, bioinformatics