scholarly journals Novel Strategy to Combat Antibiotic Resistance: A Sight into the Combination of CRISPR/Cas9 and Nanoparticles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 352
Author(s):  
Fen Wan ◽  
Mohamed S. Draz ◽  
Mengjie Gu ◽  
Wei Yu ◽  
Zhi Ruan ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Health And Safety ◽  
Multidrug Resistant ◽  
Delivery Methods ◽  
Nanoparticle Delivery ◽  
Targeting Ability ◽  
Novel Strategy ◽  
New Strategies

Antibiotic resistance is a significant crisis that threatens human health and safety worldwide. There is an urgent need for new strategies to control multidrug-resistant (MDR) bacterial infections. The latest breakthrough in gene-editing tools based on CRISPR/Cas9 has potential application in combating MDR bacterial infections because of their high targeting ability to specifically disrupt the drug resistance genes that microbes use for infection or to kill the pathogen directly. Despite the potential that CRISPR/Cas9 showed, its further utilization has been hampered by undesirable delivery efficiency in vivo. Nanotechnology offers an alternative way to overcome the shortcomings of traditional delivery methods of therapeutic agents. Advances in nanotechnology can improve the efficacy and safety of CRISPR/Cas9 components by using customized nanoparticle delivery systems. The combination of CRISPR/Cas9 and nanotechnology has the potential to open new avenues in the therapy of MDR bacterial infections. This review describes the recent advances related to CRISPR/Cas9 and nanoparticles for antimicrobial therapy and gene delivery, including the improvement in the packaging and localizing efficiency of the CRISPR/Cas9 components in the NP (nanoparticle)/CRISPR system. We pay particular attention to the strengths and limitations of the nanotechnology-based CRISPR/Cas9 delivery system to fight nosocomial pathogens.We highlight the need for more scientific research to explore the combinatorial efficacy of various nanoparticles and CRISPR technology to control and prevent antimicrobial resistance.

scholarly journals Conjugative Delivery of CRISPR-Cas9 for the Selective Depletion of Antibiotic-Resistant Enterococci

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Marinelle Rodrigues ◽  
Sara W. McBride ◽  
Karthik Hullahalli ◽  
Kelli L. Palmer ◽  
Breck A. Duerkop
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Conjugative Plasmid ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Resistance Determinants

ABSTRACT The innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) that are recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiont Enterococcus faecalis is associated with HAIs, and some strains are MDR. Therefore, novel strategies to control E. faecalis populations are needed. We previously characterized an E. faecalis type II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here, we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers to E. faecalis for the selective removal of antibiotic resistance genes. Using in vitro competition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistant E. faecalis by several orders of magnitude. Finally, we show that E. faecalis donor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinants in vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.

scholarly journals Phage-Encoded Endolysins

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 124
Author(s):  
Fatma Abdelrahman ◽  
Maheswaran Easwaran ◽  
Oluwasegun I. Daramola ◽  
Samar Ragab ◽  
Stephanie Lynch ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Wall ◽  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Therapeutic Strategies ◽  
Therapeutic Application ◽  
Significant Evidence ◽  
Crucial Information

Due to the global emergence of antibiotic resistance, there has been an increase in research surrounding endolysins as an alternative therapeutic. Endolysins are phage-encoded enzymes, utilized by mature phage virions to hydrolyze the cell wall from within. There is significant evidence that proves the ability of endolysins to degrade the peptidoglycan externally without the assistance of phage. Thus, their incorporation in therapeutic strategies has opened new options for therapeutic application against bacterial infections in the human and veterinary sectors, as well as within the agricultural and biotechnology sectors. While endolysins show promising results within the laboratory, it is important to document their resistance, safety, and immunogenicity for in-vivo application. This review aims to provide new insights into the synergy between endolysins and antibiotics, as well as the formulation of endolysins. Thus, it provides crucial information for clinical trials involving endolysins.

scholarly journals Evaluation of the Efficacy of a Bacteriophage in the Treatment of Pneumonia Induced by Multidrug ResistanceKlebsiella pneumoniaein Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Fang Cao ◽  
Xitao Wang ◽  
Linhui Wang ◽  
Zhen Li ◽  
Jian Che ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Burst Size ◽  
Multidrug Resistant ◽  
Lung Lesion ◽  
Lytic Bacteriophage ◽  
Short Latent Period ◽  
Dose Dependent ◽  
Antibiotic Control

Multidrug-resistantKlebsiella pneumoniae(MRKP) has steadily grown beyond antibiotic control. However, a bacteriophage is considered to be a potential antibiotic alternative for treating bacterial infections. In this study, a lytic bacteriophage, phage 1513, was isolated using a clinical MRKP isolate KP 1513 as the host and was characterized. It produced a clear plaque with a halo and was classified as Siphoviridae. It had a short latent period of 30 min, a burst size of 264 and could inhibit KP 1513 growthin vitrowith a dose-dependent pattern. Intranasal administration of a single dose of 2 × 109 PFU/mouse 2 h after KP 1513 inoculation was able to protect mice against lethal pneumonia. In a sublethal pneumonia model, phage-treated mice exhibited a lower level ofK. pneumoniaeburden in the lungs as compared to the untreated control. These mice lost less body weight and exhibited lower levels of inflammatory cytokines in their lungs. Lung lesion conditions were obviously improved by phage therapy. Therefore, phage 1513 has a great effectin vitroandin vivo, which has potential to be used as an alternative to an antibiotic treatment of pneumonia that is caused by the multidrug-resistantK. pneumoniae.

scholarly journals Antibiotics in Food Chain: The Consequences for Antibiotic Resistance

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 688
Author(s):  
Shashi B. Kumar ◽  
Shanvanth R. Arnipalli ◽  
Ouliana Ziouzenkova
Keyword(s):  
Public Health ◽  
Antibiotic Resistance ◽  
Food Chain ◽  
Bacterial Infections ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Alternative Strategies ◽  
Antibiotic Resistant ◽  
Continuous Use

Antibiotics have been used as essential therapeutics for nearly 100 years and, increasingly, as a preventive agent in the agricultural and animal industry. Continuous use and misuse of antibiotics have provoked the development of antibiotic resistant bacteria that progressively increased mortality from multidrug-resistant bacterial infections, thereby posing a tremendous threat to public health. The goal of our review is to advance the understanding of mechanisms of dissemination and the development of antibiotic resistance genes in the context of nutrition and related clinical, agricultural, veterinary, and environmental settings. We conclude with an overview of alternative strategies, including probiotics, essential oils, vaccines, and antibodies, as primary or adjunct preventive antimicrobial measures or therapies against multidrug-resistant bacterial infections. The solution for antibiotic resistance will require comprehensive and incessant efforts of policymakers in agriculture along with the development of alternative therapeutics by experts in diverse fields of microbiology, biochemistry, clinical research, genetic, and computational engineering.

scholarly journals Thermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Guangchao Qing ◽  
Xianxian Zhao ◽  
Ningqiang Gong ◽  
Jing Chen ◽  
Xianlei Li ◽  
...  
Keyword(s):  
Near Infrared ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Limited Effect ◽  
Bacterial Membranes ◽  
Change Mechanism ◽  
Drug Resistant Bacteria ◽  
New Strategies

Abstract New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.

scholarly journals Bacterial infections in cirrhosis: a narrative review and key points for clinical practice

2020 ◽  
Vol 14 (3) ◽  
pp. 126-135
Author(s):  
Mario Mitra ◽  
Andrea Mancuso ◽  
Flavia Politi ◽  
Alberto Maringhini
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Empirical Therapy ◽  
Multidrug Resistant ◽  
High Rate ◽  
First Episode ◽  
Bacterial Peritonitis ◽  
Prophylactic Measures ◽  
Tract Infections ◽  
Healthcare Associated

Bacterial infections are frequent complications of liver cirrhosis, accounting for severe clinical courses, and increased mortality. The reduction of the negative clinical impact of infections may be achieved by a combination of prophylactic measures to reduce the occurrence, early identification, and management. Spontaneous bacterial peritonitis (SBP), urinary tract infections, pneumonia, cellulitis, and spontaneous bacteremia are frequent in cirrhosis. The choice of initial empirical antimicrobial therapy should be based on both site, severity, and origin of infection (community-acquired, nosocomial, or healthcare-associated) and on antibiotic resistance patterns. 3rd generation cephalosporins are generally indicated as empirical therapy in most community-acquired cases. However, for nosocomial and healthcare-associated infections, due to a high rate of multidrug-resistant (MDR) pathogens, a broader spectrum treatment is appropriate. In order to prevent antibiotic resistance emergence, microbiological cultures should be collected, and a de-escalation applied when antimicrobial susceptibility tests are available. Standard measures to prevent infections and the identification of carriers of MDR bacteria are essential strategies to prevent infections in cirrhosis. Antibiotic prophylaxis should be applied only to gastrointestinal bleeding, SBP recurrence prevention, and cirrhotics at high risk of a first episode of SBP.

scholarly journals Clavanin A Improves Outcome of Complications from Different Bacterial Infections

2014 ◽  
Vol 59 (3) ◽  
pp. 1620-1626 ◽  
Author(s):  
Osmar N. Silva ◽  
Isabel C. M. Fensterseifer ◽  
Elaine A. Rodrigues ◽  
Hortência H. S. Holanda ◽  
Natasha R. F. Novaes ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Toxicity Tests ◽  
Cytotoxic Activities ◽  
Content Type ◽  
Wound Model ◽  
Acute Toxicity Tests

ABSTRACTThe rapid increase in the incidence of multidrug-resistant infections today has led to enormous interest in antimicrobial peptides (AMPs) as suitable compounds for developing unusual antibiotics. In this study, clavanin A, an antimicrobial peptide previously isolated from the marine tunicateStyela clava, was selected as a purposeful molecule that could be used in controlling infection and further synthesized. Clavanin A wasin vitroevaluated againstStaphylococcus aureusandEscherichia colias well as toward L929 mouse fibroblasts and skin primary cells (SPCs). Moreover, this peptide was challenged here in anin vivowound and sepsis model, and the immune response was also analyzed. Despite displaying clearin vitroantimicrobial activity toward Gram-positive and -negative bacteria, clavanin A showed no cytotoxic activities against mammalian cells, and in acute toxicity tests, no adverse reaction was observed at any of the concentrations. Moreover, clavanin A significantly reduced theS. aureusCFU in an experimental wound model. This peptide also reduced the mortality of mice infected withE. coliandS. aureusby 80% compared with that of control animals (treated with phosphate-buffered saline [PBS]): these data suggest that clavanin A prevents the start of sepsis and thereby reduces mortality. These data suggest that clavanin A is an AMP that could improve the development of novel peptide-based strategies for the treatment of wound and sepsis infections.

scholarly journals Curcumin Analogues as a Potential Drug against Antibiotic Resistant Protein, β-Lactamases and L, D-Transpeptidases Involved in Toxin Secretion in Salmonella typhi: A Computational Approach

2021 ◽  
Vol 2 (1) ◽  
pp. 77-100
Author(s):  
Tanzina Akter ◽  
Mahim Chakma ◽  
Afsana Yeasmin Tanzina ◽  
Meheadi Hasan Rumi ◽  
Mst. Sharmin Sultana Shimu ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Typhoid Fever ◽  
Homology Modeling ◽  
Salmonella Typhi ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
In Vivo Experiments ◽  
Curcumin Analogs

Typhoid fever caused by the bacteria Salmonella typhi gained resistance through multidrug-resistant S. typhi strains. One of the reasons behind β-lactam antibiotic resistance is -lactamase. L, D-Transpeptidases is responsible for typhoid fever as it is involved in toxin release that results in typhoid fever in humans. A molecular modeling study of these targeted proteins was carried out by various methods, such as homology modeling, active site prediction, prediction of disease-causing regions, and by analyzing the potential inhibitory activities of curcumin analogs by targeting these proteins to overcome the antibiotic resistance. The five potent drug candidate compounds were identified to be natural ligands that can inhibit those enzymes compared to controls in our research. The binding affinity of both the Go-Y032 and NSC-43319 were found against β-lactamase was −7.8 Kcal/mol in AutoDock, whereas, in SwissDock, the binding energy was −8.15 and −8.04 Kcal/mol, respectively. On the other hand, the Cyclovalone and NSC-43319 had an equal energy of −7.60 Kcal/mol in AutoDock, whereas −7.90 and −8.01 Kcal/mol in SwissDock against L, D-Transpeptidases. After the identification of proteins, the determination of primary and secondary structures, as well as the gene producing area and homology modeling, was accomplished. The screened drug candidates were further evaluated in ADMET, and pharmacological properties along with positive drug-likeness properties were observed for these ligand molecules. However, further in vitro and in vivo experiments are required to validate these in silico data to develop novel therapeutics against antibiotic resistance.

scholarly journals Conjugative delivery of CRISPR-Cas9 for the selective depletion of antibiotic-resistant enterococci

2019 ◽  
Author(s):  
Marinelle Rodrigues ◽  
Sara W. McBride ◽  
Karthik Hullahalli ◽  
Kelli L. Palmer ◽  
Breck A. Duerkop
Keyword(s):  
Antibiotic Resistance ◽  
Enterococcus Faecalis ◽  
Resistance Genes ◽  
Bacterial Infections ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Conjugative Plasmid ◽  
Antibiotic Resistant ◽  
Resistance Determinants

AbstractThe innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiontEnterococcus faecalisis associated with HAIs and some strains are MDR. Therefore, novel strategies to controlE. faecalispopulations are needed. We previously characterized anE. faecalisType II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers toE. faecalisfor the selective removal of antibiotic resistance genes. Usingin vitrocompetition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistantE. faecalisby several orders of magnitude. Finally, we show thatE. faecalisdonor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinantsin vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.ImportanceCRISPR-Cas nucleic acid targeting systems hold promise for the amelioration of multidrug-resistant enterococci, yet the utility of such tools in the context of the intestinal environment where enterococci reside is understudied. We describe the development of a CRISPR-Cas antimicrobial, deployed on a conjugative plasmid, for the targeted removal of antibiotic resistance genes from intestinalEnterococcus faecalis. We demonstrate that CRISPR-Cas targeting reduces antibiotic resistance ofE. faecalisby several orders of magnitude in the intestine. Although barriers exist that influence the penetrance of the conjugative CRISPR-Cas antimicrobial among target recipientE. faecaliscells, the removal of antibiotic resistance genes inE. faecalisupon uptake of the CRISPR-Cas antimicrobial is absolute. In addition, cells that obtain the CRISPR-Cas antimicrobial are immunized against the acquisition of new antibiotic resistance genes. This study suggests a potential path toward plasmid based CRISPR-Cas therapies in the intestine.

scholarly journals Is there any association between antibiotic resistance and virulence genes in Enterococcus isolates?

2019 ◽  
Vol 6 (12) ◽  
pp. 310-315
Author(s):  
Nergis Aşgın ◽  
Emre Taşkın
Keyword(s):  
Antibiotic Resistance ◽  
Virulence Genes ◽  
Multidrug Resistant ◽  
Automated System ◽  
High Frequencies ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
High Level

Objective: In this study, we aim to determine the frequency of antibiotic resistance and five virulence genes in Enterococcus species and the relationship between antibiotic resistance and virulence genes. Material and Methods: A total of 86 Enterococcus strains isolated from inpatients between 2015 and 2016 were included. Identification and antibiotic susceptibilities of strains were determined using a BD Phoenix fully automated system. The presence of virulence-associated genes (esp, gel E, asa1, hyl, and cyl) were investigated by using PCR method. Results: Of the 86 Enterococcus strains, 53 (61.6%) and 33 (38.4%) were Enterococcus faecium and Enterococcus faecalis, respectively. Vancomycin and high-level gentamicin resistance (HLGR) in E. faecalis strains were 0.6% and 60.6%, respectively. Furthermore, 52 of the 53 E. faecium strains were both vancomycin-resistant and HLGR. The frequency of esp, gel E, asa1, cyl, and hyl was 91.9%, 60.5%, 54.7%, 43%, and 26.7%, respectively.  The asa 1, cyl, and gel E genes were detected at high frequencies in vancomycin-susceptible and non-HLGR strains, whereas hyl gene was detected at high frequencies in vancomycin-resistant and HLGR strains. Conclusion: Virulence genes were more frequent in vancomycin-susceptible and non-HLGR Enterococcus strains than in the resistant strains. Although infections caused by multidrug-resistant strains are difficult to treat, it should be considered that susceptible strains have more virulence genes. This may reduce the in vivo efficacy of drugs and lead to treatment failures. Therefore, in addition to the in vitro susceptibilities of drugs, clinical efficacy should be monitored.

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