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      Antimicrobial resistance expansion in pathogens: a review of current mitigation strategies and advances towards innovative therapy

      review-article
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      JAC-Antimicrobial Resistance
      Oxford University Press

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          Abstract

          The escalating problem of antimicrobial resistance (AMR) proliferation in clinically important pathogens has become one of the biggest threats to human health and the global economy. Previous studies have estimated AMR-associated deaths and disability-adjusted life-years (DALYs) in many countries with a view to presenting a clearer picture of the global burden of AMR-related diseases. Recently, several novel strategies have been advanced to combat resistance spread. These include efflux activity inhibition, closing of mutant selection window (MSW), biofilm disruption, lytic bacteriophage particles, nanoantibiotics, engineered antimicrobial peptides, and the CRISPR-Cas9 gene-editing technique. The single or integrated deployment of these strategies has shown potentialities towards mitigating resistance and contributing to valuable therapeutic outcomes. Correspondingly, the new paradigm of personalized medicine demands innovative interventions such as improved and accurate point-of-care diagnosis and treatment to curtail AMR. The CRISPR-Cas system is a novel and highly promising nucleic acid detection and manipulating technology with the potential for application in the control of AMR. This review thus considers the specifics of some of the AMR-mitigating strategies, while noting their drawbacks, and discusses the advances in the CRISPR-based technology as an important point-of-care tool for tracking and curbing AMR in our fight against a looming ‘post-antibiotic’ era.

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          Most cited references122

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          The antimicrobial activity of nanoparticles: present situation and prospects for the future

          Nanoparticles (NPs) are increasingly used to target bacteria as an alternative to antibiotics. Nanotechnology may be particularly advantageous in treating bacterial infections. Examples include the utilization of NPs in antibacterial coatings for implantable devices and medicinal materials to prevent infection and promote wound healing, in antibiotic delivery systems to treat disease, in bacterial detection systems to generate microbial diagnostics, and in antibacterial vaccines to control bacterial infections. The antibacterial mechanisms of NPs are poorly understood, but the currently accepted mechanisms include oxidative stress induction, metal ion release, and non-oxidative mechanisms. The multiple simultaneous mechanisms of action against microbes would require multiple simultaneous gene mutations in the same bacterial cell for antibacterial resistance to develop; therefore, it is difficult for bacterial cells to become resistant to NPs. In this review, we discuss the antibacterial mechanisms of NPs against bacteria and the factors that are involved. The limitations of current research are also discussed.
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            CRISPR–Cas9 Structures and Mechanisms

            Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) systems employ the dual RNA–guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9–DNA interactions, and associated conformational changes. The use of CRISPR–Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)–CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural studies provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity, and PAM requirements and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.
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              The Biology of CRISPR-Cas: Backward and Forward

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                Author and article information

                Contributors
                Journal
                JAC Antimicrob Resist
                JAC Antimicrob Resist
                jacamr
                JAC-Antimicrobial Resistance
                Oxford University Press (US )
                2632-1823
                December 2023
                11 December 2023
                11 December 2023
                : 5
                : 6
                : dlad127
                Affiliations
                Discipline of Microbiology, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal , Private Bag X54001, Durban 4000, South Africa
                Department of Microbiology, School of Science and Technology, Babcock University , Ilishan-Remo, Nigeria
                Discipline of Microbiology, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal , Private Bag X54001, Durban 4000, South Africa
                Author notes
                Corresponding author. E-mail: martinstama@ 123456yahoo.com ; @tytymartins
                Author information
                https://orcid.org/0000-0002-4957-4609
                Article
                dlad127
                10.1093/jacamr/dlad127
                10712721
                38089461
                07235f7b-da77-4667-8922-401a7102a83d
                © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 14
                Categories
                Review
                AcademicSubjects/MED00740
                AcademicSubjects/SCI01150

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