The Impact of Colistin Resistance on the Activation of Innate Immunity by Lipopolysaccharide Modification

Avendaño-Ortíz, José; Ponce-Alonso, Manuel; Llanos-González, Emilio; Barragán-Prada, Hugo; Barbero-Herranz, Raquel; Lozano-Rodríguez, Roberto; Márquez-Garrido, Francesc J; Hernández-Pérez, José María; Morosini, Marı́a-Isabel; Cantón, Rafael; Campo, Rosa del; López-Collazo, Eduardo

doi:10.1128/iai.00012-23

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…Proteus mirabilis exhibited the highest colistin resistance (16/16; 100%) which may be due to the modification of LPS of outer membrane. 42 The frequency of colistin resistance among other Enterobacterales species was 23.1% (6/26) for Enterobacter aerogenes, 13% (6/46) for E. coli, and 11.1% (8/72) for K. pneumoniae. In another publication by Mahmoud et al 43 in Egypt, colistin resistance appeared in 42.9% of K. pneumoniae and E. coli isolates.…”

Section: Discussionmentioning

confidence: 93%

Colistin Resistance among Enterobacterales Isolates: Underlying Mechanisms and Alternative Treatment Options

Makled,

Ali,

Mahmoud

et al. 2023

J. Pure Appl. Microbiol.

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Global dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria (GNB) such as carbapenemase-producing Enterobacterales has resulted in reviving colistin as a final therapeutic alternative. Colistin resistance foretold a catastrophe. We aimed to detect the rates of carbapenems and colistin resistance among hospital-acquired Enterobacterales species, verify the underlying mechanisms and provide antibiogram for colistin-resistant isolates. The collected Enterobacterales isolates were tested for their antimicrobial susceptibility by the disk diffusion method and agar dilution was utilized for both imipenem and colistin. The production of ESβLs and carbapenemases was phenotypically assessed by the combined disk (CDT) and modified carbapenem inactivation (mCIM) tests, respectively. Possible attributes for colistin resistance were explored by detection of both plasmid- and efflux pump-mediated mechanisms. By multiplex PCR assay, carbapenem resistance (blaNDM-1 & blaOXA-48) and mobilized colistin-resistant-1 (mcr-1) genes were identified. A total of 160 Enterobacterales isolates were obtained of which 68.8% were MDR, 25% were XDR and 6.3% were pandrug-resistant (PDR) isolates with no statistically significant difference among Enterobacterales species (P> 0.05). Carbapenems resistance was detected in 41.3% (66/160) while colistin resistance was detected in 22% (36/160) of isolates. Proteus mirabilis expressed the highest rate of colistin resistance (100%; 16/16), followed by Enterobacter aerogenes (23.1%; 6/26), E. coli (13%; 6/46) and K.pneumoniae (11.1%; 8/72). One hundred percent (36/36) of colistin-resistant isolates proved efflux pump activity for colistin. However; only 2% (2/100) of tested Enterobacterales carried mcr-1 gene through molecular analysis. Colistin-resistant isolates exhibited variable susceptibility to the tested antimicrobial agents of which fosfomycin was the highest (94.1%). Efflux pump activity played a major role for colistin resistance among Enterobacterales species and fosfomycin could be a promising therapeutic option.

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Section: Discussionmentioning

confidence: 93%

Colistin Resistance among Enterobacterales Isolates: Underlying Mechanisms and Alternative Treatment Options

Makled,

Ali,

Mahmoud

et al. 2023

J. Pure Appl. Microbiol.

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“…Previous studies have shown decreased fitness and attenuated cytokine production in a Galleria mellonella infection model and reduced cytokine production in human-derived THP-1 cells infected with Escherichia coli expressing mcr-1 ( 14 ). Other modifications to LPS that confer colistin resistance, such as adding 4-amino-4-deoxy-l-arabinose (Ara4N), have been shown to enhance intracellular survival after phagocytosis and promote inflammatory signaling ( 15 ). In this study, we show that KP strains harboring the mcr-1 plasmid have an increased resistance to colistin with differential production of cytokines in human monocytes in vitro .…”

Section: Introductionmentioning

confidence: 99%

Lipid A modification of colistin-resistant Klebsiella pneumoniae does not alter innate immune response in a mouse model of pneumonia

Bhushan,

Castano,

Wong Fok Lung

et al. 2024

Infect Immun

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Polymyxin resistance in carbapenem-resistant Klebsiella pneumoniae bacteria is associated with high morbidity and mortality in vulnerable populations throughout the world. Ineffective antimicrobial activity by these last resort therapeutics can occur by transfer of mcr-1 , a plasmid-mediated resistance gene, causing modification of the lipid A portion of lipopolysaccharide (LPS) and disruption of the interactions between polymyxins and lipid A. Whether this modification alters the innate host immune response or carries a high fitness cost in the bacteria is not well established. To investigate this, we studied infection with K. pneumoniae (KP) ATCC 13883 harboring either the mcr-1 plasmid (p mcr-1 ) or the vector control (pBCSK) ATCC 13883. Bacterial fitness characteristics of mcr-1 acquisition were evaluated. Differentiated human monocytes (THP-1s) were stimulated with KP bacterial strains or purified LPS from both parent isolates and isolates harboring mcr-1 . Cell culture supernatants were analyzed for cytokine production. A bacterial pneumonia model in WT C57/BL6J mice was used to monitor immune cell recruitment, cytokine induction, and bacterial clearance in the bronchoalveolar lavage fluid (BALF). Isolates harboring mcr-1 had increased colistin MIC compared to the parent isolates but did not alter bacterial fitness. Few differences in cytokines were observed with purified LPS from mcr-1 expressing bacteria in vitro . However, in a mouse pneumonia model, no bacterial clearance defect was observed between p mcr-1 -harboring KP and parent isolates. Consistently, no differences in cytokine production or immune cell recruitment in the BALF were observed, suggesting that other mechanisms outweigh the effect of these lipid A mutations in LPS.

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Physiological consequences of inactivation of lgmB and lpxL1, two genes involved in lipid A synthesis in Bordetella bronchiseptica

Pérez-Ortega

Harten

Haagsman

et al. 2023

Research in Microbiology

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The Impact of Colistin Resistance on the Activation of Innate Immunity by Lipopolysaccharide Modification

Abstract: Colistin resistance is acquired by different lipopolysaccharide (LPS) modifications. We proposed to evaluate the of effect in vivo colistin resistance acquisition on the innate immune response.

Cited by 3 publications

References 50 publications

Colistin Resistance among Enterobacterales Isolates: Underlying Mechanisms and Alternative Treatment Options

Colistin Resistance among Enterobacterales Isolates: Underlying Mechanisms and Alternative Treatment Options

Lipid A modification of colistin-resistant Klebsiella pneumoniae does not alter innate immune response in a mouse model of pneumonia

Physiological consequences of inactivation of lgmB and lpxL1, two genes involved in lipid A synthesis in Bordetella bronchiseptica

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