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650700.9872What Are the Drivers Triggering Antimicrobial Resistance Emergence and Spread? Outlook from a One Health Perspective. Antimicrobial resistance (AMR) has emerged as a critical global public health threat, exacerbating healthcare burdens and imposing substantial economic costs. Currently, AMR contributes to nearly five million deaths annually worldwide, surpassing mortality rates of any single infectious disease. The economic burden associated with AMR-related disease management is estimated at approximately $730 billion per year. This review synthesizes current research on the mechanisms and multifaceted drivers of AMR development and dissemination through the lens of the One Health framework, which integrates human, animal, and environmental health perspectives. Intrinsic factors, including antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs), enable bacteria to evolve adaptive resistance mechanisms such as enzymatic inactivation, efflux pumps, and biofilm formation. Extrinsic drivers span environmental stressors (e.g., antimicrobials, heavy metals, disinfectants), socioeconomic practices, healthcare policies, and climate change, collectively accelerating AMR proliferation. Horizontal gene transfer and ecological pressures further facilitate the spread of antimicrobial-resistant bacteria across ecosystems. The cascading impacts of AMR threaten human health and agricultural productivity, elevate foodborne infection risks, and impose substantial economic burdens, particularly in low- and middle-income countries. To address this complex issue, the review advocates for interdisciplinary collaboration, robust policy implementation (e.g., antimicrobial stewardship), and innovative technologies (e.g., genomic surveillance, predictive modeling) under the One Health paradigm. Such integrated strategies are essential to mitigate AMR transmission, safeguard global health, and ensure sustainable development.202540558133
907710.9869The PLSDB 2025 update: enhanced annotations and improved functionality for comprehensive plasmid research. Plasmids are extrachromosomal DNA molecules in bacteria and archaea, playing critical roles in horizontal gene transfer, antibiotic resistance, and pathogenicity. Since its first release in 2018, our database on plasmids, PLSDB, has significantly grown and enhanced its content and scope. From 34 513 records contained in the 2021 version, PLSDB now hosts 72 360 entries. Designed to provide life scientists with convenient access to extensive plasmid data and to support computer scientists by offering curated datasets for artificial intelligence (AI) development, this latest update brings more comprehensive and accurate information for plasmid research, with interactive visualization options. We enriched PLSDB by refining the identification and classification of plasmid host ecosystems and host diseases. Additionally, we incorporated annotations for new functional structures, including protein-coding genes and biosynthetic gene clusters. Further, we enhanced existing annotations, such as antimicrobial resistance genes and mobility typing. To accommodate these improvements and to host the increase plasmid sets, the webserver architecture and underlying data structures of PLSDB have been re-reconstructed, resulting in decreased response times and enhanced visualization of features while ensuring that users have access to a more efficient and user-friendly interface. The latest release of PLSDB is freely accessible at https://www.ccb.uni-saarland.de/plsdb2025.202539565221
815620.9869Innovative Delivery System Combining CRISPR-Cas12f for Combatting Antimicrobial Resistance in Gram-Negative Bacteria. Antimicrobial resistance poses a significant global challenge, demanding innovative approaches, such as the CRISPR-Cas-mediated resistance plasmid or gene-curing system, to effectively combat this urgent crisis. To enable successful curing of antimicrobial genes or plasmids through CRISPR-Cas technology, the development of an efficient broad-host-range delivery system is paramount. In this study, we have successfully designed and constructed a novel functional gene delivery plasmid, pQ-mini, utilizing the backbone of a broad-host-range Inc.Q plasmid. Moreover, we have integrated the CRISPR-Cas12f system into the pQ-mini plasmid to enable gene-curing in broad-host of bacteria. Our findings demonstrate that pQ-mini facilitates the highly efficient transfer of genetic elements to diverse bacteria, particularly in various species in the order of Enterobacterales, exhibiting a broader host range and superior conjugation efficiency compared to the commonly used pMB1-like plasmid. Notably, pQ-mini effectively delivers the CRISPR-Cas12f system to antimicrobial-resistant strains, resulting in remarkable curing efficiencies for plasmid-borne mcr-1 or bla(KPC) genes that are comparable to those achieved by the previously reported pCasCure system. In conclusion, our study successfully establishes and optimizes pQ-mini as a broad-host-range functional gene delivery vector. Furthermore, in combination with the CRISPR-Cas system, pQ-mini demonstrates its potential for broad-host delivery, highlighting its promising role as a novel antimicrobial tool against the growing threat of antimicrobial resistance.202438863339
980830.9867Understanding Recent Developments in Colistin Resistance: Mechanisms, Clinical Implications, and Future Perspectives. Colistin resistance, driven by chromosomal mutations and the spread of plasmid-mediated MCR genes, has emerged as a critical challenge in combating multidrug-resistant Gram-negative bacteria. This resistance compromises the efficacy of colistin, leading to higher treatment failure rates, prolonged hospitalizations, and increased mortality. Recent studies have highlighted key mechanisms, including lipid A modifications, that enable bacteria to evade colistin's effects. The global spread of MCR genes exacerbates the issue, underlining the need for improved diagnostics and rapid detection of resistant strains to prevent adverse patient outcomes. To combat this growing threat, a multifaceted approach is essential, involving enhanced antimicrobial stewardship, stricter infection control measures, and continued research into alternative therapies and diagnostic methods. Collaborative efforts from researchers, healthcare providers, policymakers, and the pharmaceutical industry are crucial to preserving colistin's effectiveness and mitigating the broader impact on public health.202541148650
906840.9864TnCentral: a Prokaryotic Transposable Element Database and Web Portal for Transposon Analysis. We describe here the structure and organization of TnCentral (https://tncentral.proteininformationresource.org/ [or the mirror link at https://tncentral.ncc.unesp.br/]), a web resource for prokaryotic transposable elements (TE). TnCentral currently contains ∼400 carefully annotated TE, including transposons from the Tn3, Tn7, Tn402, and Tn554 families; compound transposons; integrons; and associated insertion sequences (IS). These TE carry passenger genes, including genes conferring resistance to over 25 classes of antibiotics and nine types of heavy metal, as well as genes responsible for pathogenesis in plants, toxin/antitoxin gene pairs, transcription factors, and genes involved in metabolism. Each TE has its own entry page, providing details about its transposition genes, passenger genes, and other sequence features required for transposition, as well as a graphical map of all features. TnCentral content can be browsed and queried through text- and sequence-based searches with a graphic output. We describe three use cases, which illustrate how the search interface, results tables, and entry pages can be used to explore and compare TE. TnCentral also includes downloadable software to facilitate user-driven identification, with manual annotation, of certain types of TE in genomic sequences. Through the TnCentral homepage, users can also access TnPedia, which provides comprehensive reviews of the major TE families, including an extensive general section and specialized sections with descriptions of insertion sequence and transposon families. TnCentral and TnPedia are intuitive resources that can be used by clinicians and scientists to assess TE diversity in clinical, veterinary, and environmental samples. IMPORTANCE The ability of bacteria to undergo rapid evolution and adapt to changing environmental circumstances drives the public health crisis of multiple antibiotic resistance, as well as outbreaks of disease in economically important agricultural crops and animal husbandry. Prokaryotic transposable elements (TE) play a critical role in this. Many carry "passenger genes" (not required for the transposition process) conferring resistance to antibiotics or heavy metals or causing disease in plants and animals. Passenger genes are spread by normal TE transposition activities and by insertion into plasmids, which then spread via conjugation within and across bacterial populations. Thus, an understanding of TE composition and transposition mechanisms is key to developing strategies to combat bacterial pathogenesis. Toward this end, we have developed TnCentral, a bioinformatics resource dedicated to describing and exploring the structural and functional features of prokaryotic TE whose use is intuitive and accessible to users with or without bioinformatics expertise.202134517763
669150.9863The antimicrobial resistance monitoring and research (ARMoR) program: the US Department of Defense response to escalating antimicrobial resistance. Responding to escalating antimicrobial resistance (AMR), the US Department of Defense implemented an enterprise-wide collaboration, the Antimicrobial Resistance Monitoring and Research Program, to aid in infection prevention and control. It consists of a network of epidemiologists, bioinformaticists, microbiology researchers, policy makers, hospital-based infection preventionists, and healthcare providers who collaborate to collect relevant AMR data, conduct centralized molecular characterization, and use AMR characterization feedback to implement appropriate infection prevention and control measures and influence policy. A particularly concerning type of AMR, carbapenem-resistant Enterobacteriaceae, significantly declined after the program was launched. Similarly, there have been no further reports or outbreaks of another concerning type of AMR, colistin resistance in Acinetobacter, in the Department of Defense since the program was initiated. However, bacteria containing AMR-encoding genes are increasing. To update program stakeholders and other healthcare systems facing such challenges, we describe the processes and impact of the program.201424795331
249260.9863Mobile Tigecycline Resistance: An Emerging Health Catastrophe Requiring Urgent One Health Global Intervention. Mobile tigecycline resistance (MTR) threatens the clinical efficacy of the salvage antibiotic, tigecycline (TIG) used in treating deadly infections in humans caused by superbugs (multidrug-, extensively drug-, and pandrug-resistant bacteria), including carbapenem- and colistin-resistant bacteria. Currently, non-mobile tet(X) and mobile plasmid-mediated transmissible tet(X) and resistance-nodulation-division (RND) efflux pump tmexCD-toprJ genes, conferring high-level TIG (HLT) resistance have been detected in humans, animals, and environmental ecosystems. Given the increasing rate of development and spread of plasmid-mediated resistance against the two last-resort antibiotics, colistin (COL) and TIG, there is a need to alert the global community on the emergence and spread of plasmid-mediated HLT resistance and the need for nations, especially developing countries, to increase their antimicrobial stewardship. Justifiably, MTR spread projects One Health ramifications and portends a monumental threat to global public and animal health, which could lead to outrageous health and economic impact due to limited options for therapy. To delve more into this very important subject matter, this current work will discuss why MTR is an emerging health catastrophe requiring urgent One Health global intervention, which has been constructed as follows: (a) antimicrobial activity of TIG; (b) mechanism of TIG resistance; (c) distribution, reservoirs, and traits of MTR gene-harboring isolates; (d) causes of MTR development; (e) possible MTR gene transfer mode and One Health implication; and (f) MTR spread and mitigating strategies.202235979498
666570.9863A One-Health Perspective of Antimicrobial Resistance (AMR): Human, Animals and Environmental Health. Antibiotics are essential for treating bacterial and fungal infections in plants, animals, and humans. Their widespread use in agriculture and the food industry has significantly enhanced animal health and productivity. However, extensive and often inappropriate antibiotic use has driven the emergence and spread of antimicrobial resistance (AMR), a global health crisis marked by the reduced efficacy of antimicrobial treatments. Recognized by the World Health Organization (WHO) as one of the top ten global public health threats, AMR arises when certain bacteria harbor antimicrobial resistance genes (ARGs) that confer resistance that can be horizontally transferred to other bacteria, accelerating resistance spread in the environment. AMR poses a significant global health challenge, affecting humans, animals, and the environment alike. A One-Health perspective highlights the interconnected nature of these domains, emphasizing that resistant microorganisms spread across healthcare, agriculture, and the environment. Recent scientific advances such as metagenomic sequencing for resistance surveillance, innovative wastewater treatment technologies (e.g., ozonation, UV, membrane filtration), and the development of vaccines and probiotics as alternatives to antibiotics in livestock are helping to mitigate resistance. At the policy level, global initiatives including the WHO Global Action Plan on AMR, coordinated efforts by (Food and Agriculture Organization) FAO and World Organisation for Animal Health (WOAH), and recommendations from the O'Neill Report underscore the urgent need for international collaboration and sustainable interventions. By integrating these scientific and policy responses within the One-Health framework, stakeholders can improve antibiotic stewardship, reduce environmental contamination, and safeguard effective treatments for the future.202541157271
955680.9862Recent insights into actinobacteria research in antimicrobial resistance: a review. Antimicrobial resistance (AMR) has emerged as a global health crisis, taking 4.71 million lives in the year 2021 and posing significant challenges to healthcare systems. Actinobacteria, particularly Streptomyces sp., are a well-established source of bioactive secondary metabolites, including antibiotics such as polyketides, aminoglycosides, and macrolides with activity against multidrug-resistant (MDR) bacteria. However, only 10% of the antibiotic genes are expressed, and others are silent in cryptic biosynthetic gene clusters (BGCs) that remain inactive under standard laboratory conditions. Advances in genome mining, bioinformatics tools like antiSMASH, and molecular techniques such as CRISPR-Cas have facilitated the identification of these clusters. Furthermore, innovative strategies such as co-culturing and HDAC inhibitors have shown promise in activating cryptic biosynthetic pathways to combat emerging antimicrobial resistance. Despite these advancements, the rapid evolution of resistance requires continuous research and global collaboration to ensure a sustainable pipeline of effective antibiotics. This review provides insight into actinobacteria-derived antibiotics, resistance mechanisms, and emerging biotechnological interventions to address the AMR crisis, underscoring the urgent need for multidisciplinary antibiotic discovery and stewardship efforts.202540627029
665690.9862Understanding the Evolution and Transmission Dynamics of Antibiotic Resistance Genes: A Comprehensive Review. Antibiotic resistance poses a formidable challenge to global public health, necessitating comprehensive understanding and strategic interventions. This review explores the evolution and transmission dynamics of antibiotic resistance genes, with a focus on Bangladesh. The indiscriminate use of antibiotics, compounded by substandard formulations and clinical misdiagnosis, fuels the emergence and spread of resistance in the country. Studies reveal high resistance rates among common pathogens, emphasizing the urgent need for targeted interventions and rational antibiotic use. Molecular assessments uncover a diverse array of antibiotic resistance genes in environmental reservoirs, highlighting the complex interplay between human activities and resistance dissemination. Horizontal gene transfer mechanisms, particularly plasmid-mediated conjugation, facilitate the exchange of resistance determinants among bacterial populations, driving the evolution of multidrug-resistant strains. The review discusses clinical implications, emphasizing the interconnectedness of environmental and clinical settings in resistance dynamics. Furthermore, bioinformatic and experimental evidence elucidates novel mechanisms of resistance gene transfer, underscoring the dynamic nature of resistance evolution. In conclusion, combating antibiotic resistance requires a multifaceted approach, integrating surveillance, stewardship, and innovative research to preserve the efficacy of antimicrobial agents and safeguard public health.202439113256
9600100.9862Novel "Superspreader" Bacteriophages Promote Horizontal Gene Transfer by Transformation. Bacteriophages infect an estimated 10(23) to 10(25) bacterial cells each second, many of which carry physiologically relevant plasmids (e.g., those encoding antibiotic resistance). However, even though phage-plasmid interactions occur on a massive scale and have potentially significant evolutionary, ecological, and biomedical implications, plasmid fate upon phage infection and lysis has not been investigated to date. Here we show that a subset of the natural lytic phage population, which we dub "superspreaders," releases substantial amounts of intact, transformable plasmid DNA upon lysis, thereby promoting horizontal gene transfer by transformation. Two novel Escherichia coli phage superspreaders, SUSP1 and SUSP2, liberated four evolutionarily distinct plasmids with equal efficiency, including two close relatives of prominent antibiotic resistance vectors in natural environments. SUSP2 also mediated the extensive lateral transfer of antibiotic resistance in unbiased communities of soil bacteria from Maryland and Wyoming. Furthermore, the addition of SUSP2 to cocultures of kanamycin-resistant E. coli and kanamycin-sensitive Bacillus sp. bacteria resulted in roughly 1,000-fold more kanamycin-resistant Bacillus sp. bacteria than arose in phage-free controls. Unlike many other lytic phages, neither SUSP1 nor SUSP2 encodes homologs to known hydrolytic endonucleases, suggesting a simple potential mechanism underlying the superspreading phenotype. Consistent with this model, the deletion of endonuclease IV and the nucleoid-disrupting protein ndd from coliphage T4, a phage known to extensively degrade chromosomal DNA, significantly increased its ability to promote plasmid transformation. Taken together, our results suggest that phage superspreaders may play key roles in microbial evolution and ecology but should be avoided in phage therapy and other medical applications. IMPORTANCE: Bacteriophages (phages), viruses that infect bacteria, are the planet's most numerous biological entities and kill vast numbers of bacteria in natural environments. Many of these bacteria carry plasmids, extrachromosomal DNA elements that frequently encode antibiotic resistance. However, it is largely unknown whether plasmids are destroyed during phage infection or released intact upon phage lysis, whereupon their encoded resistance could be acquired and manifested by other bacteria (transformation). Because phages are being developed to combat antibiotic-resistant bacteria and because transformation is a principal form of horizontal gene transfer, this question has important implications for biomedicine and microbial evolution alike. Here we report the isolation and characterization of two novel Escherichia coli phages, dubbed "superspreaders," that promote extensive plasmid transformation and efficiently disperse antibiotic resistance genes. Our work suggests that phage superspreaders are not suitable for use in medicine but may help drive bacterial evolution in natural environments.201728096488
8171110.9861Advancements 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
9855120.9861Conjugative IncC Plasmid Entry Triggers the SOS Response and Promotes Effective Transfer of the Integrative Antibiotic Resistance Element SGI1. The broad-host-range IncC plasmid family and the integrative mobilizable Salmonella genomic island 1 (SGI1) and its derivatives enable the spread of medically important antibiotic resistance genes among Gram-negative pathogens. Although several aspects of the complex functional interactions between IncC plasmids and SGI1 have been recently deciphered regarding their conjugative transfer and incompatibility, the biological signal resulting in the hijacking of the conjugative plasmid by the integrative mobilizable element remains unknown. Here, we demonstrate that the conjugative entry of IncC/IncA plasmids is detected at an early stage by SGI1 through the transient activation of the SOS response, which induces the expression of the SGI1 master activators SgaDC, shown to play a crucial role in the complex biology between SGI1 and IncC plasmids. Besides, we developed an original tripartite conjugation approach to directly monitor SGI1 mobilization in a time-dependent manner following conjugative entry of IncC plasmids. Finally, we propose an updated biological model of the conjugative mobilization of the chromosomal resistance element SGI1 by IncC plasmids. IMPORTANCE Antimicrobial resistance has become a major public health issue, particularly with the increase of multidrug resistance (MDR) in both animal and human pathogenic bacteria and with the emergence of resistance to medically important antibiotics. The spread between bacteria of successful mobile genetic elements, such as conjugative plasmids and integrative elements conferring multidrug resistance, is the main driving force in the dissemination of acquired antibiotic resistances among Gram-negative bacteria. Broad-host-range IncC plasmids and their integrative mobilizable SGI1 counterparts contribute to the spread of critically important resistance genes (e.g., extended-spectrum β-lactamases [ESBLs] and carbapenemases). A better knowledge of the complex biology of these broad-host-range mobile elements will help us to understand the dissemination of antimicrobial resistance genes that occurred across Gammaproteobacteria borders.202336472437
6506130.9861Mitigating antimicrobial resistance through effective hospital wastewater management in low- and middle-income countries. Hospital wastewater (HWW) is a significant environmental and public health threat, containing high levels of pollutants such as antibiotic-resistant bacteria (ARB), antibiotic-resistant genes (ARGs), antibiotics, disinfectants, and heavy metals. This threat is of particular concern in low- and middle-income countries (LMICs), where untreated effluents are often used for irrigating vegetables crops, leading to direct and indirect human exposure. Despite being a potential hotspot for the spread of antimicrobial resistance (AMR), existing HWW treatment systems in LMICs primarily target conventional pollutants and lack effective standards for monitoring the removal of ARB and ARGs. Consequently, untreated or inadequately treated HWW continues to disseminate ARB and ARGs, exacerbating the risk of AMR proliferation. Addressing this requires targeted interventions, including cost-effective treatment solutions, robust AMR monitoring protocols, and policy-driven strategies tailored to LMICs. This perspective calls for a paradigm shift in HWW management in LMIC, emphasizing the broader implementation of onsite treatment systems, which are currently rare. Key recommendations include developing affordable and contextually adaptable technologies for eliminating ARB and ARGs and enforcing local regulations for AMR monitoring and control in wastewater. Addressing these challenges is essential for protecting public health, preventing the environmental spread of resistance, and contributing to a global effort to preserve the efficacy of antibiotics. Recommendations include integrating scalable onsite technologies, leveraging local knowledge, and implementing comprehensive AMR-focused regulatory frameworks.202439944563
9817140.9861Common regions e.g. orf513 and antibiotic resistance: IS91-like elements evolving complex class 1 integrons. The ability of bacteria to procure, sometimes rearrange, and evince acquired DNA continues to impress us-even more so if this genetic plasticity involves the sequestering of antibiotic resistance genes. The acquisition of genes in bacteria is often facilitated by transposons, integrons and archetype insertion elements. Recently however, a new element, 'orf513', has been increasingly associated with class 1 integrons. Moreover, these 'complex' class 1 integrons can potentially mediate resistance to chloramphenicol, trimethoprim, aminoglycosides and tetracycline and may carry a range of beta-lactamase genes as well as the qnrA gene. Elements such as 'orf513' demonstrate IS91-like characteristics and will mobilize adjacent DNA via a process called rolling circle replication, and thus we have renamed them 'insertion sequence CRs' (ISCRs) to appropriately reflect their structure-function properties. In this article, we provide a brief description of these new and clinically important mobile elements, and how they are able to mobilize antibiotic resistance genes.200616751201
9246150.9861Horizontal Gene Transfer Systems for Spread of Antibiotic Resistance in Gram-Negative Bacteria. Antibiotic-resistant bacteria have become a significant global threat to public health due to the increasing difficulty in treatment. These bacteria acquire resistance by incorporating various antibiotic resistance genes (ARGs) through specialized gene transfer mechanisms, allowing them to evade antibiotic attacks. Conjugation, transformation, and transduction are well-established mechanisms that drive the acquisition and dissemination of ARGs in Gram-negative bacteria. In particular, the horizontal transfer of plasmids carrying multiple ARGs is highly problematic, as it can instantly convert susceptible bacteria into multidrug-resistant ones. Transduction, mediated by bacteriophages that package ARG-containing chromosomal DNA from host cells, also plays a crucial role in ARG spread without requiring direct cell-to-cell contact. Recently, a novel horizontal gene transfer (HGT) mechanism involving outer membrane vesicles (OMVs) has been identified as a key player in ARG dissemination. OMVs-nanoscale, spherical structures produced by bacteria during growth-have been found to carry small plasmids and chromosomal DNA fragments containing ARGs from their host bacteria. This newly discovered transfer process, termed "vesiduction," enables intercellular DNA exchange and further contributes to the spread of antibiotic resistance. Additionally, mobile genetic elements such as transposons, insertion sequences, and site-specific recombination systems like integrons facilitate rearrangement of ARGs, including their translocation between chromosomes and plasmids. This review explores the molecular mechanisms underlying the HGT of ARGs, with a particular focus on clinically isolated antibiotic-resistant Gram-negative bacteria.202540370256
3001160.9861IS26 and the IS26 family: versatile resistance gene movers and genome reorganizers. SUMMARYIn Gram-negative bacteria, the insertion sequence IS26 is highly active in disseminating antibiotic resistance genes. IS26 can recruit a gene or group of genes into the mobile gene pool and support their continued dissemination to new locations by creating pseudo-compound transposons (PCTs) that can be further mobilized by the insertion sequence (IS). IS26 can also enhance expression of adjacent potential resistance genes. IS26 encodes a DDE transposase but has unique properties. It forms cointegrates between two separate DNA molecules using two mechanisms. The well-known copy-in (replicative) route generates an additional IS copy and duplicates the target site. The recently discovered and more efficient and targeted conservative mechanism requires an IS in both participating molecules and does not generate any new sequence. The unit of movement for PCTs, known as a translocatable unit or TU, includes only one IS26. TU formed by homologous recombination between the bounding IS26s can be reincorporated via either cointegration route. However, the targeted conservative reaction is key to generation of arrays of overlapping PCTs seen in resistant pathogens. Using the copy-in route, IS26 can also act on a site in the same DNA molecule, either inverting adjacent DNA or generating an adjacent deletion plus a circular molecule carrying the DNA segment lost and an IS copy. If reincorporated, these circular molecules create a new PCT. IS26 is the best characterized IS in the IS26 family, which includes IS257/IS431, ISSau10, IS1216, IS1006, and IS1008 that are also implicated in spreading resistance genes in Gram-positive and Gram-negative pathogens.202438436262
4880170.9861Molecular mechanisms of tigecycline-resistance among Enterobacterales. The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.202438655285
9818180.9861ISCR elements: novel gene-capturing systems of the 21st century? "Common regions" (CRs), such as Orf513, are being increasingly linked to mega-antibiotic-resistant regions. While their overall nucleotide sequences show little identity to other mobile elements, amino acid alignments indicate that they possess the key motifs of IS91-like elements, which have been linked to the mobility ent plasmids in pathogenic Escherichia coli. Further inspection reveals that they possess an IS91-like origin of replication and termination sites (terIS), and therefore CRs probably transpose via a rolling-circle replication mechanism. Accordingly, in this review we have renamed CRs as ISCRs to give a more accurate reflection of their functional properties. The genetic context surrounding ISCRs indicates that they can procure 5' sequences via misreading of the cognate terIS, i.e., "unchecked transposition." Clinically, the most worrying aspect of ISCRs is that they are increasingly being linked with more potent examples of resistance, i.e., metallo-beta-lactamases in Pseudomonas aeruginosa and co-trimoxazole resistance in Stenotrophomonas maltophilia. Furthermore, if ISCR elements do move via "unchecked RC transposition," as has been speculated for ISCR1, then this mechanism provides antibiotic resistance genes with a highly mobile genetic vehicle that could greatly exceed the effects of previously reported mobile genetic mechanisms. It has been hypothesized that bacteria will surprise us by extending their "genetic construction kit" to procure and evince additional DNA and, therefore, antibiotic resistance genes. It appears that ISCR elements have now firmly established themselves within that regimen.200616760305
9215190.9860Bacterial type IV secretion systems and spread of antimicrobial resistance: a study of potential inhibitors to T4SS-based resistance spread. Antimicrobial resistance (AMR) is a major global health threat, mainly driven by the rapid spread of resistance genes through horizontal gene transfer (HGT). The Type IV Secretion System (T4SS) acts as a crucial molecular machinery that facilitates this process, allowing bacteria to transfer DNA, effector proteins, and virulence factors. This review systematically explores the structural and functional diversity of T4SS, its role in spreading AMR, and current methods for its inhibition. T4SS consists of a multi-protein complex that spans bacterial membranes, mediating conjugative plasmid transfer, host-pathogen interactions, and bacterial competition. Key components include ATPases, pilus structures, and membrane-associated proteins that show both conserved features and species-specific adaptations. These traits enable functional specialization across Gram-positive and Gram-negative bacteria, significantly contributing to the spread of vital resistance genes like extended-spectrum β-lactamases and carbapenemases via mobile genetic elements. Several approaches have been developed to inhibit T4SS and combat AMR. Small molecules targeting ATPase activity or protein interactions are promising, as are natural phytochemicals that interfere with conjugation. Bacteriophage therapy provides another strategy by specifically targeting plasmid-carrying bacteria. Host immune responses, such as innate immune recognition and secretory immunoglobulins, also show potential to influence T4SS activity. Although progress has been made, challenges remain, especially in developing selective inhibition methods that do not harm beneficial microbiota or host cells. Future research should focus on high-resolution structural studies to support rational drug design and preclinical testing of combination therapies that include T4SS inhibitors with existing antibiotics. Gaining a deeper understanding of T4SS regulation and host-pathogen interactions will be vital for creating targeted AMR strategies that also maintain ecological balance.202540956426