Emergent Polymyxin Resistance: End of an Era?

Li, Zekun; Cao, Yuping; Yi, Long; Liu, Jianhua; Yang, Qiwen

doi:10.1093/ofid/ofz368

Cited by 73 publications

(63 citation statements)

References 98 publications

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“…The European Antimicrobial Resistance Surveillance Network (EARS-net) reported that 29% of carbapenem resistant K. pneumoniae were also resistant to colistin, while only 3% of carbapenem susceptible K. pneumoniae were colistin resistant (CoR). Similar results were found in a retrospective study in Dubai in which 27% of carbapenem resistant K. pneumoniae were also resistant to colistin in five of their major hospitals [32].…”

Section: Colistinsupporting

confidence: 86%

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Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting

2020

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The increasing prevalence of antibiotic resistance is a threat to human health, particularly within vulnerable populations in the hospital and acute care settings. This leads to increasing healthcare costs, morbidity, and mortality. Bacteria rapidly evolve novel mechanisms of resistance and methods of antimicrobial evasion. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii have all been identified as pathogens with particularly high rates of resistance to antibiotics, resulting in a reducing pool of available treatments for these organisms. Effectively combating this issue requires both preventative and reactive measures. Reducing the spread of resistant pathogens, as well as reducing the rate of evolution of resistance is complex. Such a task requires a more judicious use of antibiotics through a better understanding of infection epidemiology, resistance patterns, and guidelines for treatment. These goals can best be achieved through the implementation of antimicrobial stewardship programs and the development and introduction of new drugs capable of eradicating multi-drug resistant Gram-negative pathogens (MDR GNB). The purpose of this article is to review current trends in MDR Gram-negative bacterial infections in the hospitalized setting, as well as current guidelines for management. Finally, new and emerging antimicrobials, as well as future considerations for combating antibiotic resistance on a global scale are discussed.

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Section: Colistinsupporting

confidence: 86%

“…A fecal study of livestock animals in Poland, Taiwan, China, and Switzerland found that colistin resistance is highest among animals. Resistance can easily spread to humans through ingestion of fecal contamination and horizontal gene transfer among host bacteria [32].…”

Section: Colistinmentioning

confidence: 99%

Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting

2020

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“…Colistin-resistant Enterobacteriaceae has become a great concern to global public health [5,6]. While several mechanisms of resistance have been elucidated, the most important one is mediated by the transferrable mcr-1 gene, which encodes the phosphoethanolamine transferase and it could be rapidly disseminated through the conjugative plasmid [7].…”

Section: Introductionmentioning

confidence: 99%

Characteristics of a Colistin-Resistant Escherichia coli ST695 Harboring the Chromosomally-Encoded mcr-1 Gene

Peng

et al. 2019

Microorganisms

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Enterobacteriaceae having chromosomally-encoded mcr-1 is rarely reported. In this study, we recovered a chromosomal mcr-1 carrying Escherichia coli, designated HeN100, from the feces of a diarrheal pig in China. Antimicrobial susceptibility testing showed that HeN100 was resistant to three aminoglycosides, twelve β-lactams including three carbapenems, one phenicol, two tetracyclines, two fluoroquinolones, nitrofurantoin, and colistin tested. Oxford Nanopore MinION sequencing revealed that the complete genomes of the multidrug resistant (MDR) HeN100 consisted of a single circular chromosome and five circular plasmids. Bioinformatical analysis determined HeN100 as ST695 and it contained many acquired resistance genes responsible for its MDR phenotypes, including colistin resistance mcr-1 and the carbapenem resistance blaNDM-1, and most of these genes were located on plasmids. However, the mcr-1 was found on the chromosome, and it was located between an IS30-like element ISApl1 and a PAP2-like encoding gene. These three genes consisted of an “ISApl1-mcr-1-orf” segment and inserted in high AT-rich regions. Finally, we found the blaNDM-1 was carried on an IncFII type conjugative plasmid. The conjugation frequency of this plasmid was 7.61 ± 2.11 × 10−5 per recipient, and its conjugation conferred resistance to carbapenems and other β-lactams, as well as aminoglycosides. The spread of this mcr-1/blaNDM-1-carrying E. coli ST695 represents a great concern of public health.

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“…Since the first report of mcr-1 in IncI2-type plasmid pHNSHP45, a series of mcr-1-carrying plasmids have been detected, including IncHI2, 18 IncX4, 19 IncX2, 20 IncP, 21 IncII, 22 and other. 3,23 The plasmids can act as reservoirs of horizontal gene transfer. Therefore, plasmid curing is an attractive strategy to slow the spread of colistin resistance in bacteria.…”

Section: Discussionmentioning

confidence: 99%

Reversal of mcr-1-Mediated Colistin Resistance in Escherichia coli by CRISPR-Cas9 System

Wan¹,

Cui²,

Zhi-gang³

et al. 2020

IDR

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The plasmid-borne mobilized colistin resistance gene (mcr-1) was discovered in 2015. Subsequently, the rapid horizontal transfer of mcr-1 gene to diverse bacterial species poses a serious threat to public health, which urgently needs the introduction of novel antimicrobial strategies. Therefore, the purpose of this study is to sensitize bacteria to colistin and reduce the propagation of mcr-1 gene by curing mcr-1-harboring plasmid in Escherichia coli (E. coli) using the CRISPR-Cas9 system. Methods: Two sgRNAs specific to mcr-1 gene were designed and cloned into plasmid pCas9. The recombinant plasmid pCas9-mcr was transformed into E. coli carrying pUC19mcr-1 or pHNSHP45, separately. The elimination efficiency in strains was evaluated by PCR and quantitative real-time PCR (qPCR). The antimicrobial susceptibility test was performed using the broth microdilution method. Results: In this study, we constructed the high copy number plasmid pUC19-mcr-1 and recombinant plasmid pCas9-m1 or pCas9-m2, which contain 20 nt or 30 nt sgRNA sequences targeted to mcr-1, respectively. PCR and qPCR results showed that mcr-1-harboring plasmids could be efficiently eliminated, and there was no significant correlation between sgRNA lengths and curing efficiency. However, when comparing restructured high copy number plasmid (pUC19-mcr-1) to natural resistance plasmid (pHNSHP45) in eliminating efficiency, we found that the content of plasmid backbone had an influence on efficiency. Furthermore, the conjugation assays verified that the engineered CRISPR-Cas9 system in bacteria or in bacteria genome can protect the recipient from plasmid-borne mcr-1 transfer via conjugation. Additionally, sequence analysis showed that three different types of defects in CRISPR-Cas9 system lead to escape mutants. Conclusion: We presented a method that only one plasmid-mediated CRISPR-Cas9 system can be used to efficiently resensitize E. coli to colistin. Moreover, this system provided a great potentiality to counteract the propagation of mcr-1 among bacterial pathogens.

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Emergent Polymyxin Resistance: End of an Era?

Cited by 73 publications

References 98 publications

Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting

Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting

Characteristics of a Colistin-Resistant Escherichia coli ST695 Harboring the Chromosomally-Encoded mcr-1 Gene

<p>Reversal of <em>mcr-1</em>-Mediated Colistin Resistance in <em>Escherichia coli</em> by CRISPR-Cas9 System</p>

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