Genetic and structural basis of colistin resistance in Klebsiella pneumoniae: Unravelling the molecular mechanisms

• DOI: 10.1016/j.jgar.2024.06.019
• Publication Date: 2024-07-17T22:03:04Z
• Authors: Sahar Alousi; Jamal Saad; Balig Panossian; Rita Makhlouf; Charbel Al Khoury; Kelven Rahy; Sergio Thoumi; George F. Araj; Rony Khnayzer; Sima Tokajian
• Keywords: Klebsiella pneumoniae; Lipid A modifications; mgrB; Colistin resistance; Heteroresistance; Microbiology; QR1-502; IS elements

AbstractAntimicrobial 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 pneumoniaeisolates.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 CRK. pneumoniaeisolates, 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 ofmgrBlocus revealed the presence of insertion sequences that disrupted themgrBlocus 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 themgrBgene leading to elevated MIC values and treatment failure. IS monitoring inK. pneumoniaecould help prevent the spread of colistin resistance and decrease colistin treatment failure.