The Application of the CRISPR-Cas System in Antibiotic Resistance

Tao, Shuan; Chen, Huimin; Li, Na; Liang, Wei

doi:10.2147/idr.s370869

Cited by 36 publications

(26 citation statements)

References 151 publications

(192 reference statements)

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“…Mobile genetic elements, such as insert sequences (ISs), transposons (Tns) and integrons, play an important role in increasing antibiotic resistance ( Partridge et al, 2018 ). Bacteria share MGEs and their associated resistance genes with other bacterial species via horizontal gene transfer (HGT), which has promoted the accumulation and dissemination of antibiotic resistance genes (ARGs) in bacteria ( Tao et al, 2022 ). Integrons constitute an important and near-ubiquitous class of genetic elements.…”

Section: Introductionmentioning

confidence: 99%

Class 1 integrons and multiple mobile genetic elements in clinical isolates of the Klebsiella pneumoniae complex from a tertiary hospital in eastern China

Wang

Zhu²,

Yan³

et al. 2023

Front. Microbiol.

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BackgroundThe emergence of highly drug-resistant K. pneumoniae, has become a major public health challenge. In this work, we aim to investigate the diversity of species and sequence types (STs) of clinical Klebsiella isolates and to characterize the prevalence and structure of class 1 integrons.MethodsBased on the whole genome sequencing, species identification was performed by 16S rRNA gene homology and average nucleotide identity (ANI) analysis. STs were determined in accordance with the international MLST schemes for K. pneumoniae and K. variicola. Integron characterization and comparative genomic analysis were performed using various bioinformatic tools.ResultsSpecies identification showed that the 167 isolates belonged to four species: K. pneumoniae, K. variicola subsp. variicola, K. quasipneumoniae and K. aerogenes. Thirty-six known and 5 novel STs were identified in K. pneumoniae, and 10 novel STs were identified in K. variicola subsp. variicola. Class 1 integrons were found in 57.49% (96/167) of the isolates, and a total of 169 resistance gene cassettes encoding 19 types of resistance genes, including carbapenem resistance gene (blaIPM-4) and class D β-lactamases gene (blaOXA-1 and blaOXA-10), were identified. Among the 17 complete genomes, 29 class 1 integrons from 12 groups were found, only 1 group was encoded on chromosomes. Interestingly, one plasmid (pKP167-261) carrying two copies of approximately 19-kb IS26-Int1 complex resistance region that contains an integron and a multidrug resistance gene fragment.ConclusionThe results of this work demonstrated that the species and STs of the clinical Klebsiella isolates were more complex by the whole genome sequence analysis than by the traditional laboratory methods. Finding of the new structure of MGEs related to the resistance genes indicates the great importance of deeply exploring the molecular mechanisms of bacterial multidrug resistance.

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Section: Introductionmentioning

confidence: 99%

Class 1 integrons and multiple mobile genetic elements in clinical isolates of the Klebsiella pneumoniae complex from a tertiary hospital in eastern China

Wang

Zhu²,

Yan³

et al. 2023

Front. Microbiol.

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“…The emergence of drug-resistant bacteria has greatly reduced the efficacy of current antibiotics, resulting in increased morbidity, mortality, and healthcare costs. To address this challenge, underexploited targets such as MurA have been identified as promising alternatives to novel antibacterial methods, such as the CRISPR-Cas system . Covalent inhibition of MurA, for example, with the clinically used fosfomycin, is a validated strategy for antibacterial drug development.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MurA Enzyme from Escherichia coli by Flavonoids and Their Synthetic Analogues

Frlan,

Hrast,

Gobec

2023

ACS Omega

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MurA catalyzes the first step of peptidoglycan (PG) biosynthesis and is a validated target for the development of new antimicrobial agents. In this study, a library of 49 plant flavonoids and their synthetic derivatives were evaluated for their inhibitory properties against MurA fromEscherichia coli. The compounds were tested with and without preincubation and with the addition of DTT to understand the mechanism of inhibition. Thirteen compounds were identified as reversible, time-dependent inhibitors, with inhibition levels ranging from 480 nM to 57 μM, and ampelopsin as the most potent compound. To investigate the major pharmacophore elements responsible for the activity, 2D-QSAR and docking analyzes were performed. The results showed that the catechol moiety and an additional aromatic system were the most important features contributing to the activity of the compounds. However, most of the compounds did not show antibacterial activity againstE. coli andStaphylococcus aureusstrains, suggesting that their inhibitory activity against MurA may not be strong enough to induce antibacterial effects. Nevertheless, our results suggest that flavonoids are a promising starting point to develop new inhibitors of MurA and show great potential for further steps in drug development.

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“…Type III CRISPR mechanisms demonstrated indiscriminate targeting for DNA cleavage, unlike the Type II CRISPR system, which relies on the Cas9 nuclease to cut specific DNA sequences . Therefore, the rational design of CRISPR-based tools like novel antibiotics has shown strong inclinations toward using Cas9 nucleases . However, the heavy reliance on these specific machinery raises concerns about future resistance mechanisms.…”

Section: Bacterial Mechanisms Of Resistancementioning

confidence: 99%

CRISPR-Cas-Based Antimicrobials: Design, Challenges, and Bacterial Mechanisms of Resistance

et al. 2023

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The emergence of antibiotic-resistant bacterial strains is a source of public health concern across the globe. As the discovery of new conventional antibiotics has stalled significantly over the past decade, there is an urgency to develop novel approaches to address drug resistance in infectious diseases. The use of a CRISPR-Cas-based system for the precise elimination of targeted bacterial populations holds promise as an innovative approach for new antimicrobial agent design. The CRISPR-Cas targeting system is celebrated for its high versatility and specificity, offering an excellent opportunity to fight antibiotic resistance in pathogens by selectively inactivating genes involved in antibiotic resistance, biofilm formation, pathogenicity, virulence, or bacterial viability. The CRISPR-Cas strategy can enact antimicrobial effects by two approaches: inactivation of chromosomal genes or curing of plasmids encoding antibiotic resistance. In this Review, we provide an overview of the main CRISPR-Cas systems utilized for the creation of these antimicrobials, as well as highlighting promising studies in the field. We also offer a detailed discussion about the most commonly used mechanisms for CRISPR-Cas delivery: bacteriophages, nanoparticles, and conjugative plasmids. Lastly, we address possible mechanisms of interference that should be considered during the intelligent design of these novel approaches.

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The Application of the CRISPR-Cas System in Antibiotic Resistance

Cited by 36 publications

References 151 publications

Class 1 integrons and multiple mobile genetic elements in clinical isolates of the Klebsiella pneumoniae complex from a tertiary hospital in eastern China

Class 1 integrons and multiple mobile genetic elements in clinical isolates of the Klebsiella pneumoniae complex from a tertiary hospital in eastern China

Inhibition of MurA Enzyme from Escherichia coli by Flavonoids and Their Synthetic Analogues

CRISPR-Cas-Based Antimicrobials: Design, Challenges, and Bacterial Mechanisms of Resistance

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