Low Level of Colistin Resistance and mcr Genes Presence in Salmonella spp.: Evaluation of Isolates Collected between 2000 and 2020 from Animals and Environment

Bertelloni, Fabrizio; Cagnoli, Giulia; Turchi, Barbara; Ebani, Valentina Virginia

doi:10.3390/antibiotics11020272

Cited by 9 publications

(5 citation statements)

References 33 publications

(78 reference statements)

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“…Our results highlight the problematic nature of measuring colistin resistance in the lab, consistent with several studies that found that the presence of mcr-9 gene is not sufficient to confer colistin resistance [50,74,75]. Nevertheless, over-expression of mcr-9 consistently generates clinically relevant resistance in E. coli [44].…”

Section: Discussionsupporting

confidence: 87%

Plasmid-encoded lactose metabolism and mobilized colistin resistance (mcr-9) genes in Salmonella enterica serovars isolated from dairy facilities in the 1980s

Kröger,

Lerminiaux,

Ershova

et al. 2023

Microbial Genomics

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Horizontal gene transfer by plasmids can confer metabolic capabilities that expand a host cell’s niche. Yet, it is less understood whether the coalescence of specialized catabolic functions, antibiotic resistances and metal resistances on plasmids provides synergistic benefits. In this study, we report whole-genome assembly and phenotypic analysis of five Salmonella enterica strains isolated in the 1980s from milk powder in Munich, Germany. All strains exhibited the unusual phenotype of lactose-fermentation and encoded either of two variants of the lac operon. Surprisingly, all strains encoded the mobilized colistin resistance gene 9 (mcr-9), long before the first report of this gene in the literature. In two cases, the mcr-9 gene and the lac locus were linked within a large gene island that formed an IncHI2A-type plasmid in one strain but was chromosomally integrated in the other strain. In two other strains, the mcr-9 gene was found on a large IncHI1B/IncP-type plasmid, whereas the lac locus was encoded on a separate chromosomally integrated plasmidic island. The mcr-9 sequences were identical and genomic contexts could not explain the wide range of colistin resistances exhibited by the Salmonella strains. Nucleotide variants did explain phenotypic differences in motility and exopolysaccharide production. The observed linkage of mcr-9 to lactose metabolism, an array of heavy-metal detoxification systems, and other antibiotic resistance genes may reflect a coalescence of specialized phenotypes that improve the spread of colistin resistance in dairy facilities, much earlier than previously suspected.

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Section: Discussionsupporting

confidence: 87%

Plasmid-encoded lactose metabolism and mobilized colistin resistance (mcr-9) genes in Salmonella enterica serovars isolated from dairy facilities in the 1980s

Kröger,

Lerminiaux,

Ershova

et al. 2023

Microbial Genomics

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“…Up to date, there are ten different versions of the mcr gene (mcr-1 to mcr-10) found in bacteria from various sources, including humans, animals, and the environment [10,11]; however, only the catalytic domains of MCR-1 and MCR-2 have been reported in the PDB databank. The full-length crystal structure of lipid A phosphoethanolamine transferase (EptA), which belongs to the same protein family as MCRs, suggested that the transmembrane domain is also needed for PEA hydrolysis [12].…”

Section: Introductionmentioning

confidence: 99%

Prediction of substrate binding on mobile colistin resistance using in silico approach

Hanpaibool¹,

Maitarad²,

Rungrotmongkol³

2023

ScienceAsia

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Colistin, an antibiotic, has become a last-resort therapy for serious infections caused by Antimicrobial Resistance (AMR) diseases during the last decade. The positively charged colistin coupled to the negatively charged lipid A can rupture the outer cell membrane of Gram-negative bacteria. However, the presence of a mobile colistin resistance gene (mcr gene) in Enterobacteriaceae has resulted in colistin resistance. MCR function transfers phosphoethanolamine (PEA) of phosphatidylethanolamine (PE) to lipid A, neutralizing its negative charge and preventing the binding of positively charged colistin. Currently, mcr isoforms varied from mcr-1 to mcr-10 have been discovered in environmental and clinical isolates, but only the three-dimensional structures of the catalytic portion of two MCR proteins, MCR-1 and MCR-2, were crystallized. Full-length MCR protein structures may be necessary for understanding MCR function and developing inhibitors; therefore, the structures of MCR-1 to 10 proteins were predicted by novel accurate protein prediction utilizing Deep Learning (RoseTTAFold). Based on multiple-sequence alignment and superposition on all MCR protein structures, there are six conserved residues at the active site, HIS 1 , HIS 2 , HIS 3 , ASP, GLU, and THR. Tunnel analysis was utilized to determine the possible routes for substrate PE entering into MCR proteins. Among the four substrate-binding paths to the MCR active site (tunnels 1-4), PE preferentially binds at the active site via tunnel 1. This discovery not only anticipates PE as a substrate-binding to MCR protein, but it might also be beneficial for guiding MCR inhibitors.

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“…Furthermore, epidemiological studies have shown that mcr was likely present well before its 2016 report and consequently has spread much further than initially anticipated. 3 The increased utilization of ventilators globally, especially in the context of extended usage related to severe severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection, is likely only to exacerbate the problem of resistance among nosocomial gram-negatives moving forward. 4 Combination regimens are common among chemotherapy, in general, and occur more frequently when chemotherapy is being used to target resistant cell-types.…”

mentioning

confidence: 99%

“…Since then, scientists have uncovered numerous isolates that were clinically untreatable due to resistance. Furthermore, epidemiological studies have shown that mcr was likely present well before its 2016 report and consequently has spread much further than initially anticipated 3 . The increased utilization of ventilators globally, especially in the context of extended usage related to severe severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection, is likely only to exacerbate the problem of resistance among nosocomial gram‐negatives moving forward 4 …”

mentioning

confidence: 99%

Machine Learning‐Led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram‐Negative Bacteria

Smith,

Nguyen,

Lodise

et al. 2023

Clin Pharma and Therapeutics

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Developing optimized regimens for combination antibiotic therapy is challenging and often performed empirically over many clinical studies. Novel implementation of a hybrid machine‐learning pharmacokinetic/pharmacodynamic/toxicodynamic (ML‐PK/PD/TD) approach optimizes combination therapy using human PK/TD data along with in vitro PD data. This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro PDs from the Hollow Fiber Infection Model (HFIM) to derive optimal multi‐drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism‐based PD model was constructed based on 7‐day HFIM experiments across 4 clinical, extensively drug resistant Klebsiella pneumoniae isolates. GA‐led optimization was performed using 13 different fitness functions to compare the effects of different efficacy (60%, 70%, 80%, or 90% of simulated subjects achieving bacterial counts of 102 CFU/mL) and toxicity (66% of simulated subjects having a target polymyxin B area under the concentration‐time curve [AUC] of 100 mg·h/L and aztreonam AUC of 1,332 mg·h/L) on the optimized regimen. All regimens, except those most heavily weighted for toxicity prevention, were able to achieve the target efficacy threshold (102 CFU/mL). Overall, GA‐based regimen optimization using preclinical data from animal‐sparing in vitro studies and human PopPK produced clinically relevant dosage regimens similar to those developed empirically over many years for all three antibiotics. Taken together, these data provide significant insight into new therapeutic approaches incorporating ML to regimen design and treatment of resistant bacterial infections.

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Low Level of Colistin Resistance and mcr Genes Presence in Salmonella spp.: Evaluation of Isolates Collected between 2000 and 2020 from Animals and Environment

Cited by 9 publications

References 33 publications

Plasmid-encoded lactose metabolism and mobilized colistin resistance (mcr-9) genes in Salmonella enterica serovars isolated from dairy facilities in the 1980s

Plasmid-encoded lactose metabolism and mobilized colistin resistance (mcr-9) genes in Salmonella enterica serovars isolated from dairy facilities in the 1980s

Prediction of substrate binding on mobile colistin resistance using in silico approach

Machine Learning‐Led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram‐Negative Bacteria

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