Genetic Mechanisms Of Resistance Research Articles

Integration of Genetic Resistance Mechanisms in Sustainable Crop Breeding Programs-A Review

The integration of genetic resistance mechanisms into sustainable crop breeding programs is critical for addressing global agricultural challenges, including the increasing threats posed by pests, diseases, and climate change. Genetic resistance, which involves the use of innate plant defense mechanisms, provides an environmentally friendly alternative to chemical controls and plays a pivotal role in enhancing crop resilience. Advances in molecular biology, such as CRISPR-Cas9 gene editing and multi-omics technologies (genomics, transcriptomics, and metabolomics), have revolutionized resistance breeding, enabling the precise identification, modification, and deployment of resistance traits. These tools facilitate the development of crops with enhanced resistance to biotic and abiotic stresses while reducing yield penalties and linkage drag. Challenges such as the evolution of pathogen virulence, the breakdown of race-specific resistance genes, and the trade-offs between resistance and crop quality remain significant hurdles. Durable resistance, achieved by combining qualitative and quantitative resistance traits, offers a promising approach to mitigate these issues and delay resistance breakdown. Agroecological practices, such as crop diversification, companion planting, and organic amendments, can complement genetic resistance by reducing pathogen pressure and improving ecosystem stability. International research collaborations, such as those led by CGIAR, along with local capacity-building efforts, are essential to ensure the equitable dissemination of resistance technologies, particularly in resource-limited regions. Despite these advances, socioeconomic and regulatory barriers, including public skepticism toward genetically engineered crops and stringent approval processes for GMOs and gene-edited varieties, hinder widespread adoption. Increased investments in breeding research, streamlined regulatory frameworks, and policies promoting resistant varieties are vital to overcoming these challenges. As the global demand for food continues to rise amidst climate uncertainties, the integration of cutting-edge genetic tools, ecological principles, and collaborative efforts offers a pathway to more sustainable and resilient agricultural systems. By addressing current limitations and leveraging emerging technologies, genetic resistance can significantly contribute to global food security and the sustainability of modern farming practices.

Antibody-Drug Conjugates in Breast Cancer: The Road Towards Biologically-Informed Selection and Sequencing.

In this review, we discuss evidence supporting the use of antibody-drug conjugates (ADCs) in breast cancer treatment, describe novel ADCs and combination regimens under development, and examine our current understanding of resistance mechanisms and biomarkers to guide ADC selection and sequencing. Three ADCs have proven benefit in patients with metastatic breast cancer: trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG). There are over two hundred investigational ADCs on the horizon, as pre-clinical studies work to identify novel ADC targets and structures. In this new frontier, translational efforts are underway to personalize the use of ADCs, including refining HER2 quantification and elucidating genetic, epigenetic, and post-translational mechanisms of resistance. ADCs have provided important treatment options for patients with breast cancer. As patients become eligible for more than one ADC, there is an unmet need to identify the appropriate timing and sequence of these therapies to maximize their efficacy.

Peculiarities of Emergence, Development and Genetic Mechanisms of Resistance Manifestation Towards Fungicides from the Chemical Classes of Triazoles and Strobilurins Among the Representatives of <i>Zymoseptoria tritici</i> (A Review)

Grain production serves as an important strategic resource of the Russian Federation, it is a fundamental branch of agricultural production. In order to get a high and stable yield, it is necessary to carry out protective measures for crops against various diseases. In recent years, leaf-stem diseases of grain crops stand out as the most harmful ones in agrocoenoses. They significantly decrease crop yield. Not only do they rapidly spread around multiple regions of the Russian Federation, but they encompass other grain-producing countries as well. Zymoseptoria tritici is a dangerous fungal phytopathogen that causes Septoria blotches among wheat, triticale, barley and rye. Within several decades, some significant progress has been made in the process of genetic control of wheat resistance to Z. tritici. However, due to the presence of favorable weather conditions contributing to the development of fungal infections, in order to prevent crop loss together with decrease in the quality of agricultural produce, from one to several fungicide treatments have to be implemented. Russian and foreign scientists have noted a tendency of Z. tritici to increase rersistance to some fungicides, which poses a problem with the successful implementation of efficient plant protection measures. Such classes as triazoles and strobilurins are no exception, and according to the FRAC rating, the risk of developing resistance to them is assessed as medium in the former and high in the latter, accordingly. Increasing problems caused by fungicide resistance in Z. tritici populations pose a threat to further wheat production. The purpose of the present research is to analyze modern literature data on the emergence of resistance to fungicides from the chemical classes of triazoles and strobilurins in Z. tritici. The given review examines the genetic mechanisms of resistance that appear in the phytopathogen; examples of monitoring studies of fungal resistance in various countries are provided alongside with practical recommendations on the implementation of anti-resistance strategies. The success of creating such strategies is impossible without knowledge of the pathogen population structure, cultivar resistance, regional agro-ecological peculiarities of the pathogen development and crop cultivation or the biological commercial and economic efficiency of protection means and methods.

Mapping of resistance genes to powdery mildew based on DNA re-sequencing and bulk segregant analysis in Capsicum.

Powdery mildew caused by Leveillula taurica adversely affects the development and growth of pepper plants. However, there have been few reports on the fine mapping and quantitative trait locus (QTLs) gene cloning of resistance genes to powdery mildew in pepper. Herein, an F2 segregating population was constructed using the high resistance material "NuMex Suave Red" and the extremely susceptible material "c89" for bulked segregant analysis and DNA re-sequencing (BSA-seq). Molecular markers were used to achieve fine mapping, followed by expression verification. A major QTL located on chromosome 5 (Chr5, 7.20-11.75Mb) that is associated with resistance to powdery mildew in pepper was mapped using BSA-seq. A narrow interval of 64.86kb encompassing five genes was refined using InDel and KSAP molecular markers developed from the QTL region. Among them, the expression of the ubiquitin-conjugating enzyme E2 gene, Capana05g000392, was significantly upregulated in multiple resistant materials. In addition, there was a single nucleotide polymorphism (SNP) of A/G in the 241st position of the CDS sequence of Capana05g000392, which in turn leads to an amino acid polymorphism of M/V between susceptible parent and resistant parent. Overall, these results indicate that the Capana05g000392 gene may serve as a robust potential factor against powdery mildew in pepper. These findings further elucidate the genetic mechanism of resistance to powdery mildew in pepper and facilitate molecular marker-assisted breeding.

A Review on Genetic Mechanisms of Plant-pathogen Resistance in Crop Breeding

Plant-pathogen resistance is a critical component of sustainable agriculture, essential for protecting crops from devastating diseases and ensuring global food security. This review explores the genetic mechanisms underlying plant-pathogen resistance, focusing on advances in breeding strategies and genetic engineering. Resistance (R) genes, the cornerstone of plant immunity, are categorized by their structural features, including nucleotide-binding site-leucine-rich repeat (NBS-LRR) domains, and function through pathways such as Effector-Triggered Immunity (ETI). The salicylic acid (SA) pathway, crucial for Systemic Acquired Resistance (SAR), and the jasmonic acid (JA) and ethylene (ET) pathways, which drive Induced Systemic Resistance (ISR), are pivotal in orchestrating plant defense responses. Emerging molecular tools like CRISPR-Cas9 enable precise gene editing to enhance R gene function and target susceptibility (S) genes, offering novel pathways to engineer durable resistance. Transgenic approaches, including the introduction of novel R genes and the expression of antimicrobial proteins, have expanded the genetic toolkit for combating pathogens. RNA interference (RNAi) technology further allows for the silencing of critical pathogen genes, adding a layer of defense. Traditional breeding methods, such as hybridization and backcrossing, remain integral, particularly when combined with Marker-Assisted Selection (MAS) and Genomic Selection (GS). MAS facilitates the efficient incorporation of resistance traits using molecular markers, while GS leverages genome-wide data to predict resistance, significantly enhancing breeding efficiency. Challenges such as the rapid evolution of pathogens, resistance breakdown, and climate change-induced shifts in disease dynamics pose significant threats. These challenges necessitate an integrated approach, combining genetic and genomic tools with sustainable disease management practices, such as the use of beneficial microorganisms, precision agriculture, and diversified cropping systems. Future research must focus on understanding the molecular basis of resistance durability, improving predictive models for resistance traits, and developing climate-resilient crop varieties. This integrated strategy is crucial for mitigating disease impact, enhancing crop resilience, and ensuring sustainable agricultural productivity in the face of environmental and biological challenges.

Flavin-Dependent Monooxgenase Confers Resistance to Chlorantraniliprole and Spinetoram in the Rice Stem Borer Chilo suppressalis Walker (Lepidoptera: Crambidae).

Understanding the role of flavin-containing monooxygenases (FMOs) in the genetic mechanisms of insecticide resistance is essential for developing effective management strategies against the rice stem borer, Chilo suppressalis. In this study, we identified five FMO genes in C. suppressalis, examined their expression patterns, and revealed overexpression of FMO3B and FMO3C in field populations resistant to multiple insecticides, including chlorantraniliprole and spinetoram. Functional characterization using transgenic Drosophila indicated that FMO3B and FMO3C do not confer resistance to abamectin or methoxyfenozide but do mediate resistance to chlorantraniliprole and spinetoram. Knockdown of FMO3B and FMO3C increased sensitivity to these insecticides in C. suppressalis. Molecular docking studies indicated direct binding of chlorantraniliprole and spinetoram to these FMOs, underscoring their role in metabolic resistance. These findings indicate that FMOs are key enzymes in the metabolic resistance of C. suppressalis to chlorantraniliprole and spinetoram, enhancing our understanding of insecticide resistance and aiding the development of management strategies.

Unravelling Antimicrobial Resistance in Mycoplasma hyopneumoniae: Genetic Mechanisms and Future Directions.

Antimicrobial resistance (AMR) in Mycoplasma hyopneumoniae, the causative agent of Enzootic Pneumonia in swine, poses a significant challenge to the swine industry. This review focuses on the genetic foundations of AMR in M. hyopneumoniae, highlighting the complexity of resistance mechanisms, including mutations, horizontal gene transfer, and adaptive evolutionary processes. Techniques such as Whole Genome Sequencing (WGS) and multiple-locus variable number tandem repeats analysis (MLVA) have provided insights into the genetic diversity and resistance mechanisms of M. hyopneumoniae. The study underscores the role of selective pressures from antimicrobial use in driving genomic variations that enhance resistance. Additionally, bioinformatic tools utilizing machine learning algorithms, such as CARD and PATRIC, can predict resistance traits, with PATRIC predicting 7 to 12 AMR genes and CARD predicting 0 to 3 AMR genes in 24 whole genome sequences available on NCBI. The review advocates for a multidisciplinary approach integrating genomic, phenotypic, and bioinformatics data to combat AMR effectively. It also elaborates on the need for refining genotyping methods, enhancing resistance prediction accuracy, and developing standardized antimicrobial susceptibility testing procedures specific to M. hyopneumoniae as a fastidious microorganism. By leveraging contemporary genomic technologies and bioinformatics resources, the scientific community can better manage AMR in M. hyopneumoniae, ultimately safeguarding animal health and agricultural productivity. This comprehensive understanding of AMR mechanisms will be beneficial in the adaptation of more effective treatment and management strategies for Enzootic Pneumonia in swine.

Research Progress on the Genetic and Molecular Mechanisms of Cucumber (Cucumis sativus L.) Powdery Mildew Resistance

As a common fungal disease, powdery mildew (PM) is one of the main diseases that harm the growth and development of cucumbers. Understanding the types of pathogenic fungus and analysis of the genetic and molecular mechanisms of cucumber resistance to PM at the molecular level are important when breeding disease-resistant varieties. The present review summarizes the hazards, prevention, and control of PM, and it discusses resistance inheritance rules, molecular markers, quantitative trait locus (QTL) mapping, gene cloning, omics, and gene editing technology, providing research insights on cucumber breeding varieties resistant to PM.

Multiple-resistance evolution to ACCase inhibitors and glyphosate in sourgrass (Digitaria insularis) is attributed to diverse polymorphisms in the herbicide target sites

Abstract Sourgrass [Digitaria insularis (L.) Mez ex Ekman] is considered the most troublesome weed in agronomic crops in South America. Overreliance on glyphosate has selected for resistant populations, although the resistance mechanisms remain unknown. Recently, populations were identified that exhibited multiple resistance to 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) and acetyl-CoA carboxylase (ACCase) inhibitors, posing a significant challenge due to the lack of alternative control options. This project aimed to identify the resistance patterns and levels to glyphosate and ACCase inhibitors of three suspected resistant populations (P1, P2, and P3), and elucidate the resistance mechanisms. We performed dose–response experiments with clethodim, fluazifop-P-butyl, glyphosate, and pinoxaden to identify the possibility of cross- and multiple resistance and to quantify the resistance levels. We sequenced the ACCase and EPSPS genes to test the hypothesis that target-site mutations were involved in the resistance mechanisms, given the resistance patterns observed. Our results indicated that two of the tested populations, P1 and P2, were multiple resistant to glyphosate and all ACCase-inhibitor classes, while P3 was resistant to glyphosate only. Resistance levels varied by herbicide, with resistance indices ranging from 2.7- to nearly 2,000-fold. We identified an amino acid substitution in ACCase at position 2078 (Asp-2078-Gly), homozygous for both P1 and P2, corroborating the resistance patterns observed. Interestingly, EPSPS sequencing identified multiple heterozygous DNA polymorphisms that resulted in amino acid substitutions at positions 106 (P1 and P2) or at both 102 and 106 (P3), indicating multiple evolutionary origins of glyphosate-resistance evolution. We show for the first time the genetic mechanisms of multiple resistance to glyphosate and ACCase in D. insularis, and provide a thorough discussion of the evolutionary and management implications of our work.

Extended Spectrum β-Lactamase: Tackling Antibiotic Resistance and Overcoming Treatment Challenges

Antibiotics, also known as antibacterials, kill or inhibit bacterial growth but are ineffective against viruses, fungi, or parasites, often leading to misuse. They are categorized by molecular structure, mode of action, and spectrum of activity. Antimicrobial Resistance (AMR) occurs when pathogens no longer respond to antimicrobial drugs, arising naturally or through acquisition. Resistance mechanisms include enzymatic (most common), genetic and physical. Bacteria produce various β-lactamases, such as Extended Spectrum β-lactamases (ESBLs), AmpC enzymes, and carbapenemase to exert resistance to Beta-Lactam (βL) class of antibiotics. ESBL families include TEM, SHV, and CTX-M, with E. coli being the most prevalent host. Any Gram-Negative Bacteria (GNB) can be an ESBL producer, but most common ones are the Enterobacteriaceae including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca and Proteus mirabilis. ESBL-producing Enterobacteriaceae (ESBL-E) resist penicillin, aztreonam, and cephalosporins except cephamycins and carbapenems, posing a significant public health risk. Genetic resistance mechanisms involve random mutations and horizontal gene transfer through either of the following processes namely conjugation, transformation, transduction. Physical mechanisms include efflux pump production and decreased porin channels. In some microbiological laboratories, ESBL production are often not determined, rather resistance based on MIC values to third generation Cephalosporins are considered as resistance due to ESBL production. Antibiotic use in agriculture and medicine has increased Multi-drug resistant (MDR) ESBL-producing E. coli and evidenced in retail meat and among meat shop employees. Community-acquired ESBL-E infections are a growing concern, with hospital transmission primarily occurring among patients sharing rooms with ESBL carriers. Empirical and definitive therapies for ESBL-E infections must be adjusted based on Antibiotic Susceptibility Testing (AST). The MERINO trial identified urinary tract infections as the most common source of ESBL-E bacteremia, with E. coli being predominant. For critically ill patients with non-urinary tract infections, Meropenem or Imipenem-cilastatin are recommended. For uncomplicated UTIs, Nitrofurantoin, Cotrimoxazole, and Piperacillin-Tazobactam (Pip-Taz) are effective, while Cotrimoxazole, Fluoroquinolones, and Ceftolozane-tazobactam are suitable for complicated UTIs. New β-lactamase inhibitors like avibactam, vaborbactam, and relebactam are promising for treatment. Misuse of antibiotics, such as inappropriate dosing and duration, contributes to AMR, a growing global challenge. Deaths from AMR, estimated at 1.27 million in 2019, could reach 10 million by 2050. ESBLs drive the use of broad-spectrum antibiotics, accelerating resistance development. Inadequate therapy exacerbates infections, leading to prolonged hospital stays, complications, and increased mortality. Balancing new drug development with resistance emergence is crucial to combat AMR.

Base editing screens define the genetic landscape of cancer drug resistance mechanisms

Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment.

Genetic analysis of drug resistance mechanisms and phylogenetic clustering in Candida auris isolates from Western India

Objectives: Candida auris is an emerging multidrug-resistant fungal pathogen that poses a significant threat to global health. Limited information is available from the Indian subcontinent regarding mutations associated with drug resistance and genetic variability among the isolates. In this study, we employed whole-genome sequencing (WGS) to investigate the genetic variations and drug resistance mechanisms within C. auris isolates from the western region of India. Materials and Methods: A total of twenty archived isolates were subjected to WGS on the Illumina NextSeq 2000 platform. A set of 18 genes was analyzed to check for the presence of drug-resistant mutations. Phylogenetic analysis was done using MEGA v6.06 software to identify the C. auris subgroup or clade and to check genetic relatedness among species. Statistical Analysis: The data related to drug resistance were presented in numbers and percentages. Results: Through manual analysis, drug-resistant mutations were detected in ERG11, CDR1, and TAC1b genes, which are known to be associated with reduced susceptibility to antifungal agents. Phylogenetic analysis revealed that all the isolates clustered within Clade I, indicating a high degree of genetic similarity among isolates. The absence of comprehensive antifungal mutation databases and automated tools for drug resistance detection necessitated the utilization of specialized computational skills of bioinformaticians for data analysis. Conclusions: The study provides valuable insights into the genetic diversity and drug resistance mechanisms of C. auris isolates in the western region of India and emphasizes the need for continued research and surveillance to combat this emerging pathogen. Our findings underscore the need for the development of user-friendly automated tools and comprehensive databases to facilitate rapid and accurate identification of drug resistance in C. auris.

Molecular epidemiological analysis of blaNDM-5-producing Klebsiella pneumoniae ST2407-K25 causing infection outbreaks in pediatric patients based on whole genome sequencing

BackgroundPediatric patients are vulnerable to the threat of carbapenem-resistant Klebsiella pneumoniae (CRKP) due to their limited immunity and few available antibiotics. Especially when these pathogens exhibit hypervirulent phenotypes, they are often associated with poor clinical outcomes.MethodsIn this study, we investigated a CRKP outbreak in pediatric patients from 2019 to 2021 in a teaching hospital in China based on whole genome sequencing. We sequenced twenty-nine CRKP isolates isolated from unduplicated pediatric patients to understand their genetic relationships, virulence factors, resistance mechanisms, and transmission trajectories. Conjugation experiments were performed to evaluate the horizontal transfer ability of carbapenem resistance determinants in twenty-nine CRKP isolates. We then characterized these isolates for biofilm formation ability and serum resistance. Genetic relatedness, comparison of plasmids, and chromosomal locus variation of CRKP isolates were analyzed by bioinformatics.ResultsAll the isolates were carbapenemase-producers harbouring blaNDM−5. Among them, twenty-eight isolates belonged to the ST2407 group, with the consistent capsular serotype K25. The virulence-related factors: ureA, fim, ybtA, irp1/irp2, and mrkA were prevalent in these isolates. Additionally, most CRKP isolates showed moderately adherent biofilm formation. Although the ST2407 clonal group did not exhibit serum resistance, the heterogeneous level of serum resistance was related to the disruption of oqxR. Conjugation and WGS revealed that the blaNDM−5 carried by the twenty-eight CRKP ST2407 isolates was located on nonconjugative IncX3 plasmids associated with deleting the T4SS-encoding genes. Clonal transmission of CRKP ST2407 in pediatric patients was suggested by the phylogenetic tree.ConclusionsOur study provides evidence of the clonal spread of blaNDM−5-producing K. pneumoniae in pediatric patients and the necessity for the T4SS system for horizontal transfer of the IncX3 plasmid carrying blaNDM−5. Additionally, the disruption of oqxR may have affected the serum resistance of CRKP. The results of this study emphasize the importance of continuously monitoring for CRKP infection in pediatric patients to prevent recurrent infections.

Phytochemicals as Adjuvant Therapies in RND Efflux-mediated Multidrug Resistant Pseudomonas aeruginosa Infections and Evaluation Techniques of Efflux Inhibitory Activities in Bacteria

: One of the top-listed opportunistic pathogens that are frequently found in medical devices such as ventilation systems is Pseudomonas aeruginosa. These bacteria often cause infections in the lungs (pneumonia), blood after surgery, and other parts of the body. Extreme susceptibility to P. aeruginosa infection primarily exists in immunosuppressed individuals, and long-term evolution has led to the development of genetic resistance mechanisms that have high genetic flexibility against damaging antibiotics. Several lines of research evidence point to efflux as the primary reason for the organism's effectiveness against antibiotic treat-ment in infections caused by this bacterium. Drug Efflux pumps play a crucial role in medicine because they expulse a variety of unique and unrelated chemical structures with either antibi-otics or antimicrobials before they reach the concentration necessary to kill bacteria, confer-ring multiple resistance to more than one class of antibiotics. Targeting this mechanism for example by blocking the most active efflux pump MexAB-orpM would probably lead to the discovery of new ways to circumvent the bacterial system of antibiotic resistance and boost treatment effectiveness.

Downregulation of APN1 and ABCC2 mutation in Bt Cry1Ac-resistant Trichoplusia ni are genetically independent.

The resistance to the insecticidal protein Cry1Ac from the bacterium Bacillus thuringiensis (Bt) in the cabbage looper, Trichoplusia ni, has previously been identified to be associated with a frameshift mutation in the ABC transporter ABCC2 gene and with altered expression of the aminopeptidase N (APN) genes APN1 and APN6, shown as missing of the 110-kDa APN1 (phenotype APN1¯) in larval midgut brush border membrane vesicles (BBMV). In this study, genetic linkage analysis identified that the APN1¯ phenotype and the ABCC2 mutation in Cry1Ac-resistant T. ni segregated independently, although they were always associated under Cry1Ac selection. The ABCC2 mutation and APN1¯ phenotype were separated into two T. ni strains respectively. Bioassays of the T. ni strains with Cry1Ac determined that the T. ni with the APN1¯ phenotype showed a low level resistance to Cry1Ac (3.5-fold), and the associated resistance is incompletely dominant in the background of the ABCC2 mutation. Whereas the ABCC2 mutation-associated resistance to Cry1Ac is at a moderate level, and the resistance is incompletely recessive in the genetic background of downregulated APN1. Analysis of Cry1Ac binding to larval midgut BBMV indicated that the midgut in larvae with the APN1¯ phenotype had reduced binding affinity for Cry1Ac, but the number of binding sites remained unchanged, and the midgut in larvae with the ABCC2 mutation had both reduced binding affinity and reduced number of binding sites for Cry1Ac. The reduced Cry1Ac binding to BBMV from larvae with the ABCC2 mutation or APN1¯ phenotype correlated with the lower levels of resistance.IMPORTANCEThe soil bacterium Bacillus thuringiensis (Bt) is an important insect pathogen used as a bioinsecticide for pest control. Bt genes coding for insecticidal proteins are the primary transgenes engineered into transgenic crops (Bt crops) to confer insect resistance. However, the evolution of resistance to Bt proteins in insect populations in response to exposure to Bt threatens the sustainable application of Bt biotechnology. Cry1Ac is a major insecticidal toxin utilized for insect control. Genetic mechanisms of insect resistance to Cry1Ac are complex and require to be better understood. The resistance to Cry1Ac in Trichoplusia ni is associated with a mutation in the ABCC2 gene and also associated with the APN expression phenotype APN1¯. This study identified the genetic independence of the APN1¯ phenotype from the ABCC2 mutation and isolated and analyzed the ABCC2 mutation-associated and APN1¯ phenotype-associated resistance traits in T. ni to provide new insights into the genetic mechanisms of Cry1Ac resistance in insects.

Antimicrobial resistance of Serratia marcescens causing blood stream infections in a large University Hospital in Bulgaria, an 8-year analysis (2016-2023).

The aim of this study is to evaluate the antimicrobial susceptibility of invasive isolates of Serratia marcescens, associated with blood stream infections (BSIs) in patients hospitalized in Varna University Hospital, Bulgaria, as well as to identify the genetic mechanisms responsible for 3rd generation cephalosporin and carbapenem-resistance among these isolates. A total of 45 consecutive S. marcescens isolates, obtained from blood cultures of 45 patients with BSIs, hospitalized during an 8-year period (2016-2023) were included. Species identification and antimicrobial susceptibility testing were done by Phoenix (BD, USA) and Vitek 2 (BioMerieux, France) systems and the results were interpreted according to EUCAST guidelines. The genetic mechanisms of beta-lactam resistance were studied by PCR. During the study period, a total of 45 patients were diagnosed with S. marcescens-associated BSIs. All infections were defined as nosocomial, predominantly intensive care unit-acquired (42.2%) and 28.8% were central venous catheter-associated. The following antimicrobial resistance rates were found: ceftriaxone,piperacillin/tazobactam, 57.8%; ceftazidime, 55.6%; cefepime, trimethoprime/sulfamethoxazole, 53.3%; gentamicin, 48.8%; ciprofloxacin, 44.5%; amikacin, 15.6%; carbapenems, 2.2%. TheblaCTX-M was identified in 88.9% of the tested 3rd generation cephalosporin resistant isolates. Among these, 50% were also blaTEM positive. The single carbapenem-resistant isolate harboured blaKPC, blaCTX-M1/9, blaCMY-2 and blaTEM. This study demonstrates S. marcescens as a problematic nosocomial pathogen and we report a KPC-producing S. marcescens clinical isolate from a BSI in Bulgaria.

1986P Prospective evaluation of BCG unresponsive bladder cancer carcinoma in situ identifies genetic mechanisms of immunotherapy resistance and targeted therapy using an ultra-sensitive next generation sequencing minimal residual disease (MRD) assay

1986P Prospective evaluation of BCG unresponsive bladder cancer carcinoma in situ identifies genetic mechanisms of immunotherapy resistance and targeted therapy using an ultra-sensitive next generation sequencing minimal residual disease (MRD) assay

Genetic and non-genetic resistance mechanisms in non-small cell lung cancer harboring (non-ALK) oncogenic fusions

Genetic and non-genetic resistance mechanisms in non-small cell lung cancer harboring (non-ALK) oncogenic fusions

MUTATIONS AND DRUG RESISTANCE IN MALARIA, TOXOPLASMOSIS AND GIARDIASIS: A REVIEW OF CURRENT CHALLENGES AND MECHANISMS

This study addresses the growing threat of drug resistance in malaria, toxoplasmosis, and giardiasis by analyzing the underlying genetic mutations that compromise the efficacy of current treatments. Understanding these mechanisms is crucial for developing more effective therapeutic strategies. A comprehensive review of literature was conducted to identify key mutations associated with drug resistance. In malaria, the focus was on mutations in genes like Pfmdr1, Pfcrt, Pfmrp, and Pfnhe1, which are linked to resistance against antimalarials, particularly the K76T mutation in PfCRT for chloroquine resistance. For toxoplasmosis, mutations in the DHFR-TS and DHPS genes were analyzed, particularly the T83N mutation in DHFR-TS, which confers resistance to pyrimethamine. In giardiasis, the study reviewed mutations in the ferredoxin oxidoreductase gene that reduce the efficacy of metronidazole. The analysis revealed that specific mutations in these parasites significantly contribute to the development of drug resistance, complicating treatment protocols. In malaria, PfMRP1 mutations are particularly concerning due to their role in resistance to both chloroquine and quinine. Toxoplasmosis resistance is notably influenced by DHFR-TS and DHPS mutations, while giardiasis resistance is linked to alterations in drug transport and enzyme function. This study synthesizes the most recent findings on genetic resistance mechanisms in these three parasitic diseases, offering insights that could inform the development of next-generation therapies and improve resistance management strategies, ultimately contributing to better health outcomes.

Multi-omics analysis delineates resistance mechanisms associated with BRAF inhibition in melanoma cells

Mutant BRAF is a critical oncogenic driver in melanoma, making it an attractive therapeutic target. However, the success of targeted therapy using BRAF inhibitors vemurafenib and dabrafenib has been limited due to development of resistance, restricting their clinical efficacy. A prior knowledge of resistance mechanisms to BRAFi or any cancer drug can lead to development of drugs that overcome resistance thus improving clinical outcomes. In vitro cellular models are powerful systems that can be utilized to mimic and study resistance mechanisms. In this study, we employed a multi-omics approach to characterize a panel of BRAF mutant melanoma cell lines to develop and systematically characterize BRAFi persister and resistant cells using exome sequencing, proteomics and phosphoproteomics. Our datasets revealed frequently observed intrinsic and acquired, genetic and non-genetic mechanisms of BRAFi resistance that have been studied in patients who developed resistance. In addition, we identified proteins that can be potentially targeted to overcome BRAFi resistance. Overall, we demonstrate that in vitro systems can be utilized not only to predict resistance mechanisms but also to identify putative therapeutic targets.