Elucidation of molecular mechanism for colistin resistance among Gram-negative isolates from tertiary care hospitals |
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| Institution: | 1. Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan;2. Army Medical College Rawalpindi, National University of Medical Sciences, Rawalpindi, Pakistan;3. Director Research and Head of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan;4. National University of Medical Sciences, Rawalpindi, Pakistan;1. Basaksehir Cam and Sakura City Hospital, Department of Pediatric Hematology- Oncology, Turkey;2. Istanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Division of Pediatric Emergency, Turkey;3. Gaziantep University, Faculty of Medicine, Department of Hematology, Turkey;4. Istanbul University, Istanbul Faculty of Medicine, Department of Medical Biology and Genetics, Turkey;5. University of Health Science, Istanbul Training and Research Hospital, Department of Department of Hematology, Turkey;1. Department of Infectious Diseases, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan;2. Department of Neurosurgery, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan;1. Department of Infectious Diseases, Kyoto City Hospital, Kyoto, Japan;2. Department of Clinical Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan;3. Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;4. Department of Otolaryngology, Kyoto City Hospital, Kyoto, Japan;5. Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;1. Department of Microbiology, St. Marianna University School of Medicine, Kawasaki, Japan;2. Department of Fungal Infection, National Institute of Infectious Diseases, Tokyo, Japan;3. Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan;1. Department of Microbiology, Sapporo City Institute of Public Health, Sapporo, 003-8505, Japan;2. Nakata Pediatric Clinic, Sapporo, 003-0023, Japan;3. Department of Pediatrics, KKR Sapporo Medical Center, Sapporo, 062-0931, Japan |
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| Abstract: | Antimicrobial resistance is a growing concern of global public health. The emergence of colistin-resistance among carbapenem-resistant (CPR) Gram-negative bacteria causing fear of pan-resistance, treatment failure, and high mortality across the globe.AimTo determine the genotypic colistin-resistance mechanisms among colistin-resistant (CR)Gram-negative clinical isolates along with genomic insight into hypermucoviscous(hv)-CR-Klebsiella pneumoniae.MethodsPhenotypic colistin-resistance via broth-microdilution method. PCR-based detection of plasmid-mediated colistin resistance genes(mcr-1,2,3). Characterization of selected hvCR-K. pneumoniae via Whole-genome sequencing.ResultsPhenotypic colistin-resistance was 28% among CPR-Gram-negative isolates of which 90% of CR-isolates displayed MDR profile with overall low plasmid-mediated colistin resistance (mcr-2 = 9.4%;mcr-3 = 6%). Although K. pneumoniae isolates showed the highest phenotypic colistin-resistance (51%) however, relatively low plasmid-mediated gene-carriage (mcr-2 = 11.5%;mcr-3 = 3.4%) pointed toward other mechanisms of colistin-resistance. mcr-negative CR-K. pneumoniae displaying hv-phenotype were subjected to WGS. In-silico analysis detected 7-novel mutations in lipid-A modification genes includes eptA(I38V; V50L; A135P), opgE(M53L; T486A; G236S), and arnD(S164P) in addition to several non-synonymous mutations in lipid-A modification genes conferring resistance to colistin. Insertion of 6.6-kb region harboring putative-PEA-encoding gene(yjgX) was detected for the first time in K. pneumoniae (hvCRKP4771). In-silico analysis further confirmed the acquisition of not only MDR determinants but several hypervirulent-determinants displaying a convergent phenotype.Conclusionoverall high prevalence of phenotypic colistin resistance but low mcr-gene carriage suggested complex chromosomal mediated resistance mechanism especially in K. pneumoniae isolates. The presence of novel mutations in lipid-A modification genes and the acquisition of putative-PEA-encoding gene by hvCR-K. pneumoniae points toward the role of chromosomal determinants conferring resistance to colistin in the absence of mcr-genes. |
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| Keywords: | Colistin resistance Gram-negatives Carbapenem-resistance Molecular determinants Non-synonymous mutation |
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