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In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment.
Antimicrob Agents Chemother. 2014 Aug; 58(8):4399-403.AA

Abstract

Colistin is a key drug for the treatment of infections caused by extensively drug-resistant strains of Enterobacteriaceae producing carbapenemases. However, the emergence of colistin resistance is being increasingly reported, especially among Klebsiella pneumoniae strains producing KPC-type carbapenemases (KPC-KP). In this work, we investigated colistin-susceptible (KPB-1) and colistin-resistant (KPB-2) sequential isolates obtained from a patient with a KPC-KP infection before and after low-dosage colistin treatment, respectively. By using a next-generation sequencing approach and comparative genomic analysis of the two isolates, we detected in KPB-2 a nonsynonymous nucleotide substitution in the gene encoding the PmrB sensor kinase, resulting in a leucine-to-arginine substitution at amino acid position 82. Compared with KPB-1, KPB-2 exhibited upregulated transcription of pmrA and of pmrK, which is part of the pmrHFIJKLM operon responsible for modification of the colistin lipopolysaccharide target. Complementation with wild-type pmrB in KPB-2 restored colistin susceptibility and reduced the transcription of pmrA and pmrK to basal levels, while expression of PmrB(L82R) in KPB-1 did not alter colistin susceptibility or upregulate pmrA and pmrK expression, confirming the dominance of wild-type PmrB versus the PmrB(L82R) mutant. The present results indicated that PmrB mutations mediating colistin resistance may be selected during low-dosage colistin treatment. The colistin-resistant phenotype of KPB-2 was stable for up to 50 generations in the absence of selective pressure and was not associated with a significant fitness cost in a competition experiment.

Authors+Show Affiliations

Department of Medical Biotechnologies, University of Siena, Siena, Italy.Department of Medical Biotechnologies, University of Siena, Siena, Italy.Department of Medical Biotechnologies, University of Siena, Siena, Italy.Department of Medical Biotechnologies, University of Siena, Siena, Italy.Bacteriology Laboratory, St. Orsola University Hospital, Bologna, Italy.Regional Laboratory for Microbiological Emergencies, Operative Unit of Clinical Microbiology, St. Orsola University Hospital, Bologna, Italy.Department of Medical Biotechnologies, University of Siena, Siena, Italy.Department of Medical Biotechnologies, University of Siena, Siena, Italy Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy gianmaria.rossolini@unifi.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24841267

Citation

Cannatelli, Antonio, et al. "In Vivo Evolution to Colistin Resistance By PmrB Sensor Kinase Mutation in KPC-producing Klebsiella Pneumoniae Is Associated With Low-dosage Colistin Treatment." Antimicrobial Agents and Chemotherapy, vol. 58, no. 8, 2014, pp. 4399-403.
Cannatelli A, Di Pilato V, Giani T, et al. In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment. Antimicrob Agents Chemother. 2014;58(8):4399-403.
Cannatelli, A., Di Pilato, V., Giani, T., Arena, F., Ambretti, S., Gaibani, P., D'Andrea, M. M., & Rossolini, G. M. (2014). In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment. Antimicrobial Agents and Chemotherapy, 58(8), 4399-403. https://doi.org/10.1128/AAC.02555-14
Cannatelli A, et al. In Vivo Evolution to Colistin Resistance By PmrB Sensor Kinase Mutation in KPC-producing Klebsiella Pneumoniae Is Associated With Low-dosage Colistin Treatment. Antimicrob Agents Chemother. 2014;58(8):4399-403. PubMed PMID: 24841267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment. AU - Cannatelli,Antonio, AU - Di Pilato,Vincenzo, AU - Giani,Tommaso, AU - Arena,Fabio, AU - Ambretti,Simone, AU - Gaibani,Paolo, AU - D'Andrea,Marco Maria, AU - Rossolini,Gian Maria, Y1 - 2014/05/19/ PY - 2014/5/21/entrez PY - 2014/5/21/pubmed PY - 2015/9/5/medline SP - 4399 EP - 403 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 58 IS - 8 N2 - Colistin is a key drug for the treatment of infections caused by extensively drug-resistant strains of Enterobacteriaceae producing carbapenemases. However, the emergence of colistin resistance is being increasingly reported, especially among Klebsiella pneumoniae strains producing KPC-type carbapenemases (KPC-KP). In this work, we investigated colistin-susceptible (KPB-1) and colistin-resistant (KPB-2) sequential isolates obtained from a patient with a KPC-KP infection before and after low-dosage colistin treatment, respectively. By using a next-generation sequencing approach and comparative genomic analysis of the two isolates, we detected in KPB-2 a nonsynonymous nucleotide substitution in the gene encoding the PmrB sensor kinase, resulting in a leucine-to-arginine substitution at amino acid position 82. Compared with KPB-1, KPB-2 exhibited upregulated transcription of pmrA and of pmrK, which is part of the pmrHFIJKLM operon responsible for modification of the colistin lipopolysaccharide target. Complementation with wild-type pmrB in KPB-2 restored colistin susceptibility and reduced the transcription of pmrA and pmrK to basal levels, while expression of PmrB(L82R) in KPB-1 did not alter colistin susceptibility or upregulate pmrA and pmrK expression, confirming the dominance of wild-type PmrB versus the PmrB(L82R) mutant. The present results indicated that PmrB mutations mediating colistin resistance may be selected during low-dosage colistin treatment. The colistin-resistant phenotype of KPB-2 was stable for up to 50 generations in the absence of selective pressure and was not associated with a significant fitness cost in a competition experiment. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/24841267/In_vivo_evolution_to_colistin_resistance_by_PmrB_sensor_kinase_mutation_in_KPC_producing_Klebsiella_pneumoniae_is_associated_with_low_dosage_colistin_treatment_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=24841267 DB - PRIME DP - Unbound Medicine ER -