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917400.9752Developing Phage Therapy That Overcomes the Evolution of Bacterial Resistance. The global rise of antibiotic resistance in bacterial pathogens and the waning efficacy of antibiotics urge consideration of alternative antimicrobial strategies. Phage therapy is a classic approach where bacteriophages (bacteria-specific viruses) are used against bacterial infections, with many recent successes in personalized medicine treatment of intractable infections. However, a perpetual challenge for developing generalized phage therapy is the expectation that viruses will exert selection for target bacteria to deploy defenses against virus attack, causing evolution of phage resistance during patient treatment. Here we review the two main complementary strategies for mitigating bacterial resistance in phage therapy: minimizing the ability for bacterial populations to evolve phage resistance and driving (steering) evolution of phage-resistant bacteria toward clinically favorable outcomes. We discuss future research directions that might further address the phage-resistance problem, to foster widespread development and deployment of therapeutic phage strategies that outsmart evolved bacterial resistance in clinical settings.202337268007
917310.9752Bacterial defences: mechanisms, evolution and antimicrobial resistance. Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In response to these threats, they have evolved sophisticated defence mechanisms that today also protect bacteria against antibiotics and other therapies. In this Review, we explore the protective strategies of bacteria, including the mechanisms, evolution and clinical implications of these ancient defences. We also review the countermeasures that attackers have evolved to overcome bacterial defences. We argue that understanding how bacteria defend themselves in nature is important for the development of new therapies and for minimizing resistance evolution.202337095190
816120.9748Integrative strategies against multidrug-resistant bacteria: Synthesizing novel antimicrobial frontiers for global health. Concerningly, multidrug-resistant bacteria have emerged as a prime worldwide trouble, obstructing the treatment of infectious diseases and causing doubts about the therapeutic accidentalness of presently existing drugs. Novel antimicrobial interventions deserve development as conventional antibiotics are incapable of keeping pace with bacteria evolution. Various promising approaches to combat MDR infections are discussed in this review. Antimicrobial peptides are examined for their broad-spectrum efficacy and reduced ability to develop resistance, while phage therapy may be used under extreme situations when antibiotics fail. In addition, the possibility of CRISPR-Cas systems for specifically targeting and eradicating resistance genes from bacterial populations will be explored. Nanotechnology has opened up the route to improve the delivery system of the drug itself, increasing the efficacy and specificity of antimicrobial action while protecting its host. Discovering potential antimicrobial agents is an exciting prospect through developments in synthetic biology and the rediscovery of natural product-based medicines. Moreover, host-directed therapies are now becoming popular as an adjunct to the main strategies of therapeutics without specifically targeting pathogens. Although these developments appear impressive, questions about production scaling, regulatory approvals, safety, and efficacy for clinical employment still loom large. Thus, tackling the MDR burden requires a multi-pronged plan, integrating newer treatment modalities with existing antibiotic regimens, enforcing robust stewardship initiatives, and effecting policy changes at the global level. The international health community can gird itself against the growing menace of antibiotic resistance if collaboration between interdisciplinary bodies and sustained research endeavours is encouraged. In this study, we evaluate the synergistic potential of combining various medicines in addition to summarizing recent advancements. To rethink antimicrobial stewardship in the future, we provide a multi-tiered paradigm that combines pathogen-focused and host-directed strategies.202540914328
917230.9743These Are the Genes You're Looking For: Finding Host Resistance Genes. Humanity's ongoing struggle with new, re-emerging and endemic infectious diseases serves as a frequent reminder of the need to understand host-pathogen interactions. Recent advances in genomics have dramatically advanced our understanding of how genetics contributes to host resistance or susceptibility to bacterial infection. Here we discuss current trends in defining host-bacterial interactions at the genome-wide level, including screens that harness CRISPR/Cas9 genome editing, natural genetic variation, proteomics, and transcriptomics. We report on the merits, limitations, and findings of these innovative screens and discuss their complementary nature. Finally, we speculate on future innovation as we continue to progress through the postgenomic era and towards deeper mechanistic insight and clinical applications.202133004258
958940.9743Phage Therapy: Going Temperate? Strictly lytic phages have been consensually preferred for phage therapy purposes. In contrast, temperate phages have been avoided due to an inherent capacity to mediate transfer of genes between bacteria by specialized transduction - an event that may increase bacterial virulence, for example, by promoting antibiotic resistance. Now, advances in sequencing technologies and synthetic biology are providing new opportunities to explore the use of temperate phages for therapy against bacterial infections. By doing so we can considerably expand our armamentarium against the escalating threat of antibiotic-resistant bacteria.201930466900
917950.9742A detailed landscape of CRISPR-Cas-mediated plant disease and pest management. Genome editing technology has rapidly evolved to knock-out genes, create targeted genetic variation, install precise insertion/deletion and single nucleotide changes, and perform large-scale alteration. The flexible and multipurpose editing technologies have started playing a substantial role in the field of plant disease management. CRISPR-Cas has reduced many limitations of earlier technologies and emerged as a versatile toolbox for genome manipulation. This review summarizes the phenomenal progress of the use of the CRISPR toolkit in the field of plant pathology. CRISPR-Cas toolbox aids in the basic studies on host-pathogen interaction, in identifying virulence genes in pathogens, deciphering resistance and susceptibility factors in host plants, and engineering host genome for developing resistance. We extensively reviewed the successful genome editing applications for host plant resistance against a wide range of biotic factors, including viruses, fungi, oomycetes, bacteria, nematodes, insect pests, and parasitic plants. Recent use of CRISPR-Cas gene drive to suppress the population of pathogens and pests has also been discussed. Furthermore, we highlight exciting new uses of the CRISPR-Cas system as diagnostic tools, which rapidly detect pathogenic microorganism. This comprehensive yet concise review discusses innumerable strategies to reduce the burden of crop protection.202235835393
660.9742YprA family helicases provide the missing link between diverse prokaryotic immune systems. Bacteria and archaea possess an enormous variety of antivirus immune systems that often share homologous proteins and domains, some of which contribute to diverse defense strategies. YprA family helicases are central to widespread defense systems DISARM, Dpd, and Druantia. Here, through comprehensive phylogenetic and structural prediction analysis of the YprA family, we identify several major, previously unrecognized clades, with unique signatures of domain architecture and associations with other genes. Each YprA family clade defines a distinct class of defense systems, which we denote ARMADA (disARM-related Antiviral Defense Array), BRIGADE (Base hypermodification and Restriction Involving Genes encoding ARMADA-like and Dpd-like Effectors), or TALON (TOTE-like and ARMADA-Like Operon with Nuclease). In addition to the YprA-like helicase, ARMADA systems share two more proteins with DISARM. However, ARMADA YprA homologs are most similar to those of Druantia, suggesting ARMADA is a 'missing link' connecting DISARM and Druantia. We show experimentally that ARMADA protects bacteria against a broad range of phages via a direct, non-abortive mechanism. We also discovered multiple families of satellite phage-like mobile genetic elements that often carry both ARMADA and Druantia Type III systems and show that these can provide synergistic resistance against diverse phages.202541000832
816270.9742Nanotechnology for Targeted Detection and Removal of Bacteria: Opportunities and Challenges. The emergence of nanotechnology has created unprecedented hopes for addressing several unmet industrial and clinical issues, including the growing threat so-termed "antibiotic resistance" in medicine. Over the last decade, nanotechnologies have demonstrated promising applications in the identification, discrimination, and removal of a wide range of pathogens. Here, recent insights into the field of bacterial nanotechnology are examined that can substantially improve the fundamental understanding of nanoparticle and bacteria interactions. A wide range of developed nanotechnology-based approaches for bacterial detection and removal together with biofilm eradication are summarized. The challenging effects of nanotechnologies on beneficial bacteria in the human body and environment and the mechanisms of bacterial resistance to nanotherapeutics are also reviewed.202134558234
818380.9742Modification of arthropod vector competence via symbiotic bacteria. Some of the world's most devastating diseases are transmitted by arthropod vectors. Attempts to control these arthropods are currently being challenged by the widespread appearance of insecticide resistance. It is therefore desirable to develop alternative strategies to complement existing methods of vector control. In this review, Charles Beard, Scott O'Neill, Robert Tesh, Frank Richards and Serap Aksoy present an approach for introducing foreign genes into insects in order to confer refractoriness to vector populations, ie. the inability to transmit disease-causing agents. This approach aims to express foreign anti-parasitic or anti-viral gene products in symbiotic bacteria harbored by insects. The potential use of naturally occurring symbiont-based mechanisms in the spread of such refractory phenotypes is also discussed.199315463748
918290.9741Harnessing CRISPR/Cas9 in engineering biotic stress immunity in crops. There is significant potential for CRISPR/Cas9 to be used in developing crops that can adapt to biotic stresses such as fungal, bacterial, viral, and pest infections and weeds. The increasing global population and climate change present significant threats to food security by putting stress on plants, making them more vulnerable to diseases and productivity losses caused by pathogens, pests, and weeds. Traditional breeding methods are inadequate for the rapid development of new plant traits needed to counteract this decline in productivity. However, modern advances in genome-editing technologies, particularly CRISPR/Cas9, have transformed crop protection through precise and targeted modifications of plant genomes. This enables the creation of resilient crops with improved resistance to pathogens, pests, and weeds. This review examines various methods by which CRISPR/Cas9 can be utilized for crop protection. These methods include knocking out susceptibility genes, introducing resistance genes, and modulating defense genes. Potential applications of CRISPR/Cas9 in crop protection involve introducing genes that confer resistance to pathogens, disrupting insect genes responsible for survival and reproduction, and engineering crops that are resistant to herbicides. In conclusion, CRISPR/Cas9 holds great promise for advancing crop protection and ensuring food security in the face of environmental challenges and increasing population pressures. The most recent advancements in CRISPR technology for creating resistance to bacteria, fungi, viruses, and pests are covered here. We wrap up by outlining the most pressing issues and technological shortcomings, as well as unanswered questions for further study.202540663257
8266100.9741Remarkable Mechanisms in Microbes to Resist Phage Infections. Bacteriophages (phages) specifically infect bacteria and are the most abundant biological entities on Earth. The constant exposure to phage infection imposes a strong selective pressure on bacteria to develop viral resistance strategies that promote prokaryotic survival. Thus, this parasite-host relationship results in an evolutionary arms race of adaptation and counteradaptation between the interacting partners. The evolutionary outcome is a spectrum of remarkable strategies used by the bacteria and phages as they attempt to coexist. These approaches include adsorption inhibition, injection blocking, abortive infection, toxin-antitoxin, and CRISPR-Cas systems. In this review, we highlight the diverse and complementary antiphage systems in bacteria, as well as the evasion mechanisms used by phages to escape these resistance strategies.201426958724
8163110.9740Green materials science and engineering reduces biofouling: approaches for medical and membrane-based technologies. Numerous engineered and natural environments suffer deleterious effects from biofouling and/or biofilm formation. For instance, bacterial contamination on biomedical devices pose serious health concerns. In membrane-based technologies, such as desalination and wastewater reuse, biofouling decreases membrane lifetime, and increases the energy required to produce clean water. Traditionally, approaches have combatted bacteria using bactericidal agents. However, due to globalization, a decline in antibiotic discovery, and the widespread resistance of microbes to many commercial antibiotics and metallic nanoparticles, new materials, and approaches to reduce biofilm formation are needed. In this mini-review, we cover the recent strategies that have been explored to combat microbial contamination without exerting evolutionary pressure on microorganisms. Renewable feedstocks, relying on structure-property relationships, bioinspired/nature-derived compounds, and green processing methods are discussed. Greener strategies that mitigate biofouling hold great potential to positively impact human health and safety.201525852659
8264120.9739Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity. Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here, we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage blocking the host CRISPR-Cas immune system to allow a second Acr-phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points toward higher initial phage densities. Collectively, these data help elucidate how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics.201830033365
9190130.9738Phage-based biocontrol strategies and their application in agriculture and aquaculture. Meeting global food demands for a growing human population with finite natural resources is a major challenge. Aquaculture and agriculture are critical to satisfy food requirements, yet suffer significant losses from bacterial diseases. Therefore, there is an urgent need to develop novel antimicrobial strategies, which is heightened by increasing antibiotic resistance. Bacteriophages (phages) are viruses that specifically infect bacteria, and phage-derived therapies are promising treatments in the fight against bacterial diseases. Here, we describe multiple ways that phages and phage-based technologies can be used as antimicrobials. Antimicrobial activity can be achieved through lysis of targeted bacteria by virulent phages or lytic enzymes. Alternatively, phages can be engineered for the delivery of lethal genes and other cargoes to kill bacteria and to manipulate the bacterial response to conventional antibiotics. We also briefly highlight research exploring phages as potential biocontrol agents with examples from agriculture and aquaculture.201830514766
8136140.9738Recent progress in CRISPR/Cas9-based genome editing for enhancing plant disease resistance. Nowadays, agricultural production is strongly affected by both climate change and pathogen attacks which seriously threaten global food security. For a long time, researchers have been waiting for a tool allowing DNA/RNA manipulation to tailor genes and their expression. Some earlier genetic manipulation methods such as meganucleases (MNs), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) allowed site directed modification but their successful rate was limited due to lack of flexibility when targeting a 'site-specific nucleic acid'. The discovery of clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has revolutionized genome editing domain in different living organisms during the past 9 years. Based on RNA-guided DNA/RNA recognition, CRISPR/Cas9 optimizations have offered an unrecorded scientific opportunity to engineer plants resistant to diverse pathogens. In this report, we describe the main characteristics of the primary reported-genome editing tools ((MNs, ZFNs, TALENs) and evaluate the different CRISPR/Cas9 methods and achievements in developing crop plants resistant to viruses, fungi and bacteria.202336871676
8171150.9738Advancements in CRISPR-Cas-based strategies for combating antimicrobial resistance. Multidrug resistance (MDR) in bacteria presents a significant global health threat, driven by the widespread dissemination of antibiotic-resistant genes (ARGs). The CRISPR-Cas system, known for its precision and adaptability, holds promise as a tool to combat antimicrobial resistance (AMR). Although previous studies have explored the use of CRISPR-Cas to target bacterial genomes or plasmids harboring resistance genes, the application of CRISPR-Cas-based antimicrobial therapies is still in its early stages. Challenges such as low efficiency and difficulties in delivering CRISPR to bacterial cells remain. This review provides an overview of the CRISPR-Cas system, highlights recent advancements in CRISPR-Cas-based antimicrobials and delivery strategies for combating AMR. The review also discusses potential challenges for the future development of CRISPR-Cas-based antimicrobials. Addressing these challenges would enable CRISPR therapies to become a practical solution for treating AMR infections in the future.202540440869
9185160.9737The Age of Phage: Friend or Foe in the New Dawn of Therapeutic and Biocontrol Applications? Extended overuse and misuse of antibiotics and other antibacterial agents has resulted in an antimicrobial resistance crisis. Bacteriophages, viruses that infect bacteria, have emerged as a legitimate alternative antibacterial agent with a wide scope of applications which continue to be discovered and refined. However, the potential of some bacteriophages to aid in the acquisition, maintenance, and dissemination of negatively associated bacterial genes, including resistance and virulence genes, through transduction is of concern and requires deeper understanding in order to be properly addressed. In particular, their ability to interact with mobile genetic elements such as plasmids, genomic islands, and integrative conjugative elements (ICEs) enables bacteriophages to contribute greatly to bacterial evolution. Nonetheless, bacteriophages have the potential to be used as therapeutic and biocontrol agents within medical, agricultural, and food processing settings, against bacteria in both planktonic and biofilm environments. Additionally, bacteriophages have been deployed in developing rapid, sensitive, and specific biosensors for various bacterial targets. Intriguingly, their bioengineering capabilities show great promise in improving their adaptability and effectiveness as biocontrol and detection tools. This review aims to provide a balanced perspective on bacteriophages by outlining advantages, challenges, and future steps needed in order to boost their therapeutic and biocontrol potential, while also providing insight on their potential role in contributing to bacterial evolution and survival.202133670836
9588170.9737Bacteriophage-host arm race: an update on the mechanism of phage resistance in bacteria and revenge of the phage with the perspective for phage therapy. Due to a constant attack by phage, bacteria in the environment have evolved diverse mechanisms to defend themselves. Several reviews on phage resistance mechanisms have been published elsewhere. Thanks to the advancement of molecular techniques, several new phage resistance mechanisms were recently identified. For the practical phage therapy, the emergence of phage-resistant bacteria could be an obstacle. However, unlike antibiotic, phages could evolve a mechanism to counter-adapt against phage-resistant bacteria. In this review, we summarized the most recent studies of the phage-bacteria arm race with the perspective of future applications of phages as antimicrobial agents.201930680434
9176180.9737Evolutionary Dynamics between Phages and Bacteria as a Possible Approach for Designing Effective Phage Therapies against Antibiotic-Resistant Bacteria. With the increasing global threat of antibiotic resistance, there is an urgent need to develop new effective therapies to tackle antibiotic-resistant bacterial infections. Bacteriophage therapy is considered as a possible alternative over antibiotics to treat antibiotic-resistant bacteria. However, bacteria can evolve resistance towards bacteriophages through antiphage defense mechanisms, which is a major limitation of phage therapy. The antiphage mechanisms target the phage life cycle, including adsorption, the injection of DNA, synthesis, the assembly of phage particles, and the release of progeny virions. The non-specific bacterial defense mechanisms include adsorption inhibition, superinfection exclusion, restriction-modification, and abortive infection systems. The antiphage defense mechanism includes a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system. At the same time, phages can execute a counterstrategy against antiphage defense mechanisms. However, the antibiotic susceptibility and antibiotic resistance in bacteriophage-resistant bacteria still remain unclear in terms of evolutionary trade-offs and trade-ups between phages and bacteria. Since phage resistance has been a major barrier in phage therapy, the trade-offs can be a possible approach to design effective bacteriophage-mediated intervention strategies. Specifically, the trade-offs between phage resistance and antibiotic resistance can be used as therapeutic models for promoting antibiotic susceptibility and reducing virulence traits, known as bacteriophage steering or evolutionary medicine. Therefore, this review highlights the synergistic application of bacteriophages and antibiotics in association with the pleiotropic trade-offs of bacteriophage resistance.202235884169
9578190.9736Type III secretion systems in symbiotic adaptation of pathogenic and non-pathogenic bacteria. The emergence of multi-drug resistance and bacteria with increased virulence is a familiar refrain to the contemporary microbiologist. Although intense research over the past decade has ascribed much molecular detail to these processes, more esoteric questions remain: for example, why are some bacteria evolving increased virulence towards humans, what are the genes underpinning this virulence potential and what are the selective pressures that favor these traits? A holistic approach that considers the organismal biology of bacteria with their diverse hosts seems appropriate to begin to tackle such issues. As it happens, the type III secretion system is turning out to be a central player in the adaptation of both parasites and mutualists to diverse hosts. With this in mind, human interventions in agriculture, animal husbandry and even drug discovery that could influence the selection of bacteria with improved type III secretion system function should be critically appraised.200919217298