A phylogenomic approach for the analysis of colistin resistance-associated genes in Klebsiella pneumoniae, its mutational diversity and implications for phenotypic resistance

Elias, Rita S.; Spadar, Anton; Phelan, Jody; Melo‐Cristino, José; Lito, Luı́s; Pinto, Margarida; Gonçalves, Luísa; Campino, Susana; Clark, Taane G.; Duarte, Aida; Perdigão, João

doi:10.1016/j.ijantimicag.2022.106581

Cited by 6 publications

(10 citation statements)

References 35 publications

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“…This suggests the circulation of diverse colistin-resistant genotypes responding differently to the colistin ban. We detected mutations, alone or in combination, in genes known to be involved in lipid A modifications and colistin resistance phenotypes (arnABDFT, phoQ, pmrACD and mgrB), as described (42)(43)(44)(45)(46)(47)(48)(49)(50). However, a high variety of other non-described mutations were detected, supporting the urgent need for reliable genotypic-phenotypic correlations to explain colistin resistance mechanisms (51).…”

Section: Discussionmentioning

confidence: 58%

“…Neighbour-joining trees were edited using iToL (97). Snippy v3.2-dev (https://github.com/tseemann/snippy) was used to identify substitutions (SNPs) and insertions/deletions (InDels) in genes (n=32) putatively associated with colistin resistance (43,51,98), by aligning the raw read data from each isolate against the reference genome Klebsiella pneumoniae MGH 78578 (GenBank accession number CP000647). All the gene mutations were further manually confirmed in the assembled genomes using the Geneious Prime® 2023.0.1 software (http://www.geneious.com/).…”

Section: Phenotypic and Genotypic Characterization Of K Pneumoniae Re...mentioning

confidence: 99%

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From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

Mourão

Ribeiro-Almeida

Novais

et al. 2023

Preprint

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The concern of colistin-resistant bacteria in animal-food-environmental-human ecosystems prompted the poultry sector to implement colistin restrictions and explore alternative trace metals/copper feed supplementation. The impact of these strategies on the selection and persistence of colistin-resistant Klebsiella pneumoniae (Kp) in the whole poultry-production chain needs clarification. We assessed colistin-resistant and copper-tolerant Kp occurrence in chicken raised with inorganic and organic copper-formulas from one-day-old chicks to meat (7 farms/2019-2020), after long-term colistin withdrawal (>2-years). Clonal diversity and Kp adaptive features were characterized by cultural, molecular, and whole-genome-sequencing (WGS) approaches. Most chicken-flocks (75%) carried Kp at early+pre-slaughter stages, with a significant decrease (p<0.05) in meat batches (17%) and sporadic water/feed contamination. High rates (>50%) of colistin-resistant/mcr-negative Kp were observed among faecal samples, independently of feed. Most samples carried multidrug-resistant (90%) and copper-tolerant isolates (81%; pco+sil/MICCuSO4 ≥16mM). WGS revealed accumulation of colistin resistance associated mutations and F-type multireplicon plasmids carrying antibiotic resistance and metal/copper-tolerance genes. The Kp population was polyclonal, with various lineages dispersed throughout poultry production. ST15-KL19, ST15-KL146 and ST392-KL27, and IncF plasmids were similar to those from global human clinical isolates, suggesting chicken-production as a reservoir/source of clinically-relevant Kp lineages and genes with potential risk to humans through food and/or environmental exposure. Despite long-term colistin ban limited mcr spread, it was ineffective in controlling colistin-resistant/mcr-negative Kp, regardless of feed. This study provides crucial insights into the persistence of clinically-relevant Kp in the poultry-production chain and highlights the need for continued surveillance and proactive food safety actions within a One-Health perspective.

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Section: Discussionmentioning

confidence: 58%

Section: Phenotypic and Genotypic Characterization Of K Pneumoniae Re...mentioning

confidence: 99%

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

Mourão

Ribeiro-Almeida

Novais

et al. 2023

Preprint

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“…The strains with a MIC of >16 μg/mL were defined as having high-level polymyxin resistance as previously described ( 50 ). Deleterious mutations were defined as the mutations of certain genes predicted to affect protein function using PROVEAN.…”

Section: Methodsmentioning

confidence: 99%

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

Liu

Lei

et al. 2023

Microbiol Spectr

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“…The PmrB T157P mutation has been extensively discussed, and Jayol et al (2014) confirmed that it confers colistin resistance (Elias et al, 2022;Jayol et al, 2014). On the other hand, the unique PmrB mutation G207D alongside PhoQ_ H339D has been reported to result in high levels of colistin resistance (Elias et al, 2022). A recent study has also reported PmrB mutation T246A in ~87% of colistin-resistant K. pneumoniae (COLR-Kp) ST11 isolates alongside mutation R256G (Liu et al, 2021a).…”

mentioning

confidence: 92%

“…The focus of this study was on PmrB since it plays a major role in colistin resistance by controlling PmrC to transfer phosphoethanolainme (pEtN) to lipid A. The PmrB T157P mutation has been extensively discussed, and Jayol et al (2014) confirmed that it confers colistin resistance (Elias et al, 2022;Jayol et al, 2014). On the other hand, the unique PmrB mutation G207D alongside PhoQ_ H339D has been reported to result in high levels of colistin resistance (Elias et al, 2022).…”

mentioning

confidence: 99%

Impact of PmrB mutations on clinical Klebsiella pneumoniae with variable colistin‐susceptibilities: Structural insights and potent therapeutic solutions

Basu,

Veeraraghavan,

Anbarasu

2023

Chem Biol Drug Des

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Carbapenem‐resistant Klebsiella pneumoniae (CRKP) infections continue to impose high morbidity threats to hospitalized patients worldwide, limiting therapeutic options to last‐resort antibiotics like colistin. However, the dynamic genomic landscape of colistin‐resistant K. pneumoniae (COLR‐Kp) invoked ardent exploration of underlying molecular signatures for therapeutic propositions/designs. We unveiled the structural impact of the widespread and emerging PmrB mutations involved in colistin resistance (COLR) in K. pneumoniae. In the present study, clinical isolates of K. pneumoniae expressed variable susceptibilities to colistin (>0.5 μg/mL for resistant and ≤0.25 μg/mL for susceptible) despite mutations such as T157P, G207D and T246A. The protein sequences extracted from in‐house sequenced genomes were used to model mutant PmrB proteins and analyze the underlying structural alterations. The mutations were contrasted based on molecular dynamics simulation trajectories, free‐energy landscapes and structural flexibility profiles. The altered backbone flexibilities can be an essential factor for mutant selection by COLR K. pneumoniae and can provide clues to deal with emerging mutants. Furthermore, PmrB having high druggability confidence (>0.99), was explored as a potential target for 1396 virtually screened FDA‐approved drug candidates. Among the top‐10 compounds (scores >70), amphotericin B was found to be potential candidate with high affinity (Binding energy <−8 kcal/mol) and stable interactions (RMSF <0.7 Å) against PmrB druggable pockets, despite the mutations, which encourages future adjunct therapeutic research against COLR‐Kp.

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A phylogenomic approach for the analysis of colistin resistance-associated genes in Klebsiella pneumoniae, its mutational diversity and implications for phenotypic resistance

Cited by 6 publications

References 35 publications

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

From farm to fork: persistence of clinically-relevant multidrug-resistant and copper-tolerantKlebsiella pneumoniaelong after colistin withdrawal in poultry production

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

Impact of PmrB mutations on clinical Klebsiella pneumoniae with variable colistin‐susceptibilities: Structural insights and potent therapeutic solutions

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