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bioRxiv · 10.1101/2023.08.23.554495

Genetic and Structural Basis of Colistin Resistance in Klebsiella pneumoniae: Unraveling the Molecular Mechanisms

Alousi, S.·Saad, J.·Panossian, B.·Makhlouf, R.·Al Khoury, C.·Rahy, K.·Thoumi, S.·ARAJ, G. F.·Khnayzer, R.·Tokajian, S.
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Abstract

Antimicrobial Antimicrobial resistance (AMR), together with extensively drug resistant (XDR), mainly among Gram-negative bacteria, has been on the rise. Colistin (polymyxin E) remains one of the primary available last resorts to treat infections by XDR bacteria with the rapid emergence of global resistance. Since the exact mechanism of bacterial resistance to colistin remains unfolded, this study warranted elucidating the underlying mechanism of colistin resistance and heteroresistance among carbapenem-resistant (CR) Klebsiella pneumoniae isolates. Molecular analysis was carried out on the resistant isolates using a genome-wide characterization approach, and MALDI-TOF MS for lipid A. Among the 32 CR K. pneumoniae isolates, three and seven isolates showed resistance and intermediate resistance, respectively, to colistin. The seven isolates with intermediate resistance exhibited the "skip-well" phenomenon, attributed to the presence of resistant subpopulations. The three isolates with full resistance to colistin showed ions using MALDI-TOF MS at m/z 1840 and 1824 representing bisphosphorylated and hexaacylated lipid A with or without hydroxylation, at position C-2 of the fatty acyl chain, respectively. Studying the genetic environment of mgrB locus revealed the presence of insertion sequences that disrupted the mgrB locus in the three colistin resistant isolates: IS1R and IS903B. Our findings showed that colistin resistance/heteroresistance was inducible with mutations in chromosomal regulatory networks controlling lipid A moiety and IS sequences disrupting the mgrB gene leading to elevated MIC values and treatment failure. IS monitoring in K. pneumoniae could help prevent the spread of colistin resistance and decrease colistin treatment failure.

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Alousi, S., Saad, J., Panossian, B., Makhlouf, R., Al Khoury, C., Rahy, K., Thoumi, S., ARAJ, G. F., Khnayzer, R., Tokajian, S.. 2023-08-24. Genetic and Structural Basis of Colistin Resistance in Klebsiella pneumoniae: Unraveling the Molecular Mechanisms. https://doi.org/10.1101/2023.08.23.554495

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