{"title":"肺炎克雷伯氏菌对可乐定耐药性的遗传和结构基础：揭示分子机制。","authors":"Sahar Alousi , Jamal Saad , Balig Panossian , Rita Makhlouf , Charbel Al Khoury , Kelven Rahy , Sergio Thoumi , George F. Araj , Rony Khnayzer , Sima Tokajian","doi":"10.1016/j.jgar.2024.06.019","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>Antimicrobial resistance (AMR), together with multidrug resistance (MDR), mainly among Gram-negative bacteria, has been on the rise. Colistin (polymyxin E) remains one of the primary available last resorts to treat infections caused by MDR bacteria during the rapid emergence of global resistance. As the exact mechanism of bacterial resistance to colistin remains undetermined, this study warranted elucidation of the underlying mechanisms of colistin resistance and heteroresistance among carbapenem-resistant <em>Klebsiella pneumoniae</em> isolates.</p></div><div><h3>Methods</h3><p>Molecular analysis was carried out on the resistant isolates using a genome-wide characterisation approach, as well as MALDI-TOF mass spectrometry, to identify lipid A.</p></div><div><h3>Results</h3><p>Among the 32 carbapenem-resistant <em>K. pneumoniae</em> isolates, several isolates showed resistance and intermediate resistance 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 mass spectrometry at <em>m/z</em> of 1840 and 1824 representing bisphosphorylated and hexa-acylated lipid A, respectively, with or without hydroxylation at position C’-2 of the fatty acyl chain. Studying the genetic environment of <em>mgrB</em> locus revealed the presence of two insertion sequences that disrupted the <em>mgrB</em> locus in the three colistin-resistant isolates: IS1R and IS903B.</p></div><div><h3>Conclusions</h3><p>Our findings show that colistin resistance/heteroresistance was inducible with mutations in chromosomal regulatory networks controlling the lipid A moiety and insertion sequences disrupting the <em>mgrB</em> gene, leading to elevated minimum inhibitory concentration values and treatment failure. Different treatment strategies should be employed to avoid colistin heteroresistance-linked treatment failures, mainly through combination therapy using colistin with carbapenems, aminoglycosides, or tigecycline.</p></div>","PeriodicalId":15936,"journal":{"name":"Journal of global antimicrobial resistance","volume":"38 ","pages":"Pages 256-264"},"PeriodicalIF":3.7000,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213716524001280/pdfft?md5=cd915c9fadd273bed6ecafe07b38089b&pid=1-s2.0-S2213716524001280-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Genetic and structural basis of colistin resistance in Klebsiella pneumoniae: Unravelling the molecular mechanisms\",\"authors\":\"Sahar Alousi , Jamal Saad , Balig Panossian , Rita Makhlouf , Charbel Al Khoury , Kelven Rahy , Sergio Thoumi , George F. Araj , Rony Khnayzer , Sima Tokajian\",\"doi\":\"10.1016/j.jgar.2024.06.019\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>Antimicrobial resistance (AMR), together with multidrug resistance (MDR), mainly among Gram-negative bacteria, has been on the rise. Colistin (polymyxin E) remains one of the primary available last resorts to treat infections caused by MDR bacteria during the rapid emergence of global resistance. As the exact mechanism of bacterial resistance to colistin remains undetermined, this study warranted elucidation of the underlying mechanisms of colistin resistance and heteroresistance among carbapenem-resistant <em>Klebsiella pneumoniae</em> isolates.</p></div><div><h3>Methods</h3><p>Molecular analysis was carried out on the resistant isolates using a genome-wide characterisation approach, as well as MALDI-TOF mass spectrometry, to identify lipid A.</p></div><div><h3>Results</h3><p>Among the 32 carbapenem-resistant <em>K. pneumoniae</em> isolates, several isolates showed resistance and intermediate resistance 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 mass spectrometry at <em>m/z</em> of 1840 and 1824 representing bisphosphorylated and hexa-acylated lipid A, respectively, with or without hydroxylation at position C’-2 of the fatty acyl chain. Studying the genetic environment of <em>mgrB</em> locus revealed the presence of two insertion sequences that disrupted the <em>mgrB</em> locus in the three colistin-resistant isolates: IS1R and IS903B.</p></div><div><h3>Conclusions</h3><p>Our findings show that colistin resistance/heteroresistance was inducible with mutations in chromosomal regulatory networks controlling the lipid A moiety and insertion sequences disrupting the <em>mgrB</em> gene, leading to elevated minimum inhibitory concentration values and treatment failure. Different treatment strategies should be employed to avoid colistin heteroresistance-linked treatment failures, mainly through combination therapy using colistin with carbapenems, aminoglycosides, or tigecycline.</p></div>\",\"PeriodicalId\":15936,\"journal\":{\"name\":\"Journal of global antimicrobial resistance\",\"volume\":\"38 \",\"pages\":\"Pages 256-264\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-07-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2213716524001280/pdfft?md5=cd915c9fadd273bed6ecafe07b38089b&pid=1-s2.0-S2213716524001280-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of global antimicrobial resistance\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2213716524001280\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"INFECTIOUS DISEASES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of global antimicrobial resistance","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2213716524001280","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
Genetic and structural basis of colistin resistance in Klebsiella pneumoniae: Unravelling the molecular mechanisms
Objective
Antimicrobial resistance (AMR), together with multidrug resistance (MDR), mainly among Gram-negative bacteria, has been on the rise. Colistin (polymyxin E) remains one of the primary available last resorts to treat infections caused by MDR bacteria during the rapid emergence of global resistance. As the exact mechanism of bacterial resistance to colistin remains undetermined, this study warranted elucidation of the underlying mechanisms of colistin resistance and heteroresistance among carbapenem-resistant Klebsiella pneumoniae isolates.
Methods
Molecular analysis was carried out on the resistant isolates using a genome-wide characterisation approach, as well as MALDI-TOF mass spectrometry, to identify lipid A.
Results
Among the 32 carbapenem-resistant K. pneumoniae isolates, several isolates showed resistance and intermediate resistance 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 mass spectrometry at m/z of 1840 and 1824 representing bisphosphorylated and hexa-acylated lipid A, respectively, with or without hydroxylation at position C’-2 of the fatty acyl chain. Studying the genetic environment of mgrB locus revealed the presence of two insertion sequences that disrupted the mgrB locus in the three colistin-resistant isolates: IS1R and IS903B.
Conclusions
Our findings show that colistin resistance/heteroresistance was inducible with mutations in chromosomal regulatory networks controlling the lipid A moiety and insertion sequences disrupting the mgrB gene, leading to elevated minimum inhibitory concentration values and treatment failure. Different treatment strategies should be employed to avoid colistin heteroresistance-linked treatment failures, mainly through combination therapy using colistin with carbapenems, aminoglycosides, or tigecycline.
期刊介绍：
The Journal of Global Antimicrobial Resistance (JGAR) is a quarterly online journal run by an international Editorial Board that focuses on the global spread of antibiotic-resistant microbes.
JGAR is a dedicated journal for all professionals working in research, health care, the environment and animal infection control, aiming to track the resistance threat worldwide and provides a single voice devoted to antimicrobial resistance (AMR).
Featuring peer-reviewed and up to date research articles, reviews, short notes and hot topics JGAR covers the key topics related to antibacterial, antiviral, antifungal and antiparasitic resistance.
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