Resistance Phenotype Research Articles

Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma.

As a highly heterogeneous cancer, hepatocellular carcinoma (HCC) shows different response rates to the multi-kinase inhibitor lenvatinib. Thus, it is important to explore genetic biomarkers for precision lenvatinib therapy in HCC. The effect and mechanism of AXIN1 mutation on HCC were revealed by cell proliferation assay, long-term clone formation assay, sphere formation assay and small molecule inhibitor library screening. A new therapeutic strategy targeting HCC with AXIN1 mutation was evaluated in humanized models (patient-derived xenograft [PDX] and patient-derived organoid [PDO]). Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo. AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.

Transgenic expression of SeCYP9A186 and PxFMO2 confers resistance to emamectin benzoate in Plutella xylostella.

The overexpression of metabolic enzymes constitutes a crucial mechanism for insects to detoxify xenobiotics and metabolic pesticides. A flavin-containing monooxygenase gene (PxFMO2) from Plutella xylostella and a P450 gene (SeCYP9A186, F116V mutant allele) from Spodoptera exigua have been reported to be involved in insecticide resistance. In this study, we aim to utilize transgenic technology to validate their in vivo detoxification functions in Plutella xylostella. We established two transgenic strains of Plutella xylostella with expressing an endogenous PxFMO2 gene from Plutella xylostella and an exogenous SeCYP9A186 gene from S. exigua, respectively. Bioassays demonstrated that the transgenic Plutella xylostella strain (IPP-FMO2) expressing PxFMO2 exhibited a 12-fold resistance to emamectin benzoate and a 6.4-fold resistance to chlorantraniliprole compared to the background strain (IPP-S). In contrast, the transgenic Plutella xylostella strain (IPP-9A186) expressing SeCYP9A186 displayed a 235-fold resistance to emamectin benzoate and a 115-fold resistance to abamectin. Moreover, resistance to emamectin benzoate in the IPP-9A186 strain of Plutella xylostella was inherited as an incompletely dominant trait and was genetically linked to the transgene locus. Our results not only elucidated the in vivo contribution of the PxFMO2 and SeCYP9A186 to the insecticide resistance phenotype in Plutella xylostella, but also provided a genetic engineering toolkit to manipulate resistance pathways. These insights and methodologies could further aid in developing sustainable pest management strategies in Plutella xylostella. © 2024 Society of Chemical Industry.

Thymidine Analogue Mutations with M184V Significantly Decrease Phenotypic Susceptibility of HIV-1 Subtype C Reverse Transcriptase to Islatravir

Islatravir (ISL) is the first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTtI) with novel modes of action. Data on ISL resistance are currently limited, particularly to HIV-1 non-B subtypes. This study aimed to assess prevalent nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistant mutations in HIV-1 subtype C for their phenotypic resistance to ISL. Prevalent single and combinations of NRTI-resistant mutations were selected from a routine HIV-1 genotypic drug resistance testing database and introduced into HIV-1 subtype C-like pseudoviruses, which were then tested for ISL susceptibility. Single NRTI-resistant mutations were susceptible or showed only a low level of resistance to ISL. This included thymidine analogue mutations (TAMs, i.e., M41L, D67N, K70R, T215FY, and K219EQ) and non-TAMs (i.e., A62V, K65R, K70ET, L74IV, A114S, Y115F, and M184V). Combinations of M184V with one or more additional NRTI-resistant mutations generally displayed reduced ISL susceptibilities. This was more prominent for combinations that included M184V+TAMs, and particularly M184V+TAM-2 mutations. Combinations that included M184V+K65R did not impact significantly on ISL susceptibility. Our study suggests that ISL would be effective in treating people living with HIV (PLWH) failing tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or TDF/emtricitabine (FTC)-containing regimens, but would be less effective in PLH failing zidovudine (AZT) with 3TC or FTC-containing regimens.

Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background

The emergence of Plasmodium falciparum parasites resistant to artemisinins compromises the efficacy of Artemisinin Combination Therapies (ACTs), the global first-line malaria treatment. Artemisinin resistance is a complex genetic trait in which nonsynonymous SNPs in PfK13 cooperate with other genetic variations. Here, we present population genomic/transcriptomic analyses of P. falciparum collected from patients with uncomplicated malaria in Cambodia and Vietnam between 2018 and 2020. Besides the PfK13 SNPs, several polymorphisms, including nonsynonymous SNPs (N1131I and N821K) in PfRad5 and an intronic SNP in PfWD11 (WD40 repeat-containing protein on chromosome 11), appear to be associated with artemisinin resistance, possibly as new markers. There is also a defined set of genes whose steady-state levels of mRNA and/or splice variants or antisense transcripts correlate with artemisinin resistance at the base level. In vivo transcriptional responses to artemisinins indicate the resistant parasite’s capacity to decelerate its intraerythrocytic developmental cycle (IDC), which can contribute to the resistant phenotype. During this response, PfRAD5 and PfWD11 upregulate their respective alternatively/aberrantly spliced isoforms, suggesting their contribution to the protective response to artemisinins. PfRAD5 and PfWD11 appear under selective pressure in the Greater Mekong Sub-region over the last decade, suggesting their role in the genetic background of the artemisinin resistance.

Revisiting mutational resistance to ampicillin and cefotaxime in Haemophilus influenzae

BackgroundHaemophilus influenzae is an opportunistic bacterial pathogen that can cause severe respiratory tract and invasive infections. The emergence of β-lactamase-negative ampicillin-resistant (BLNAR) strains and unclear correlations between genotypic (i.e., gBLNAR) and phenotypic resistance are challenging empirical treatments and patient management. Thus, we sought to revisit molecular resistance mechanisms and to identify new resistance determinants of H. influenzae.MethodsWe performed a systematic meta-analysis of H. influenzae isolates (n = 291) to quantify the association of phenotypic ampicillin and cefotaxime resistance with previously defined resistance groups, i.e., specific substitution patterns of the penicillin binding protein PBP3, encoded by ftsI. Using phylogenomics and a genome-wide association study (GWAS), we investigated evolutionary trajectories and novel resistance determinants in a public global cohort (n = 555) and a new clinical cohort from three European centers (n = 298), respectively.ResultsOur meta-analysis confirmed that PBP3 group II- and group III-related isolates were significantly associated with phenotypic resistance to ampicillin (p < 0.001), while only group III-related isolates were associated with resistance to cefotaxime (p = 0.02). The vast majority of H. influenzae isolates not classified into a PBP3 resistance group were ampicillin and cefotaxime susceptible. However, particularly group II isolates had low specificities (< 16%) to rule in ampicillin resistance due to clinical breakpoints classifying many of them as phenotypically susceptible. We found indications for positive selection of multiple PBP3 substitutions, which evolved independently and often step-wise in different phylogenetic clades. Beyond ftsI, other possible candidate genes (e.g., oppA, ridA, and ompP2) were moderately associated with ampicillin resistance in the GWAS. The PBP3 substitutions M377I, A502V, N526K, V547I, and N569S were most strongly related to ampicillin resistance and occurred in combination in the most prevalent resistant haplotype H1 in our clinical cohort.ConclusionsGradient agar diffusion strips and broth microdilution assays do not consistently classify isolates from PBP3 groups as phenotypically resistant. Consequently, when the minimum inhibitory concentration is close to the clinical breakpoints, and genotypic data is available, PBP3 resistance groups should be prioritized over susceptible phenotypic results for ampicillin. The implications on treatment outcome and bacterial fitness of other extended PBP3 substitution patterns and novel candidate genes need to be determined.

Drought and heat stress studies in perennial ryegrass: a bibliometric analysis 1994–2024

Perennial ryegrass (Lolium perenne L.) is a key forage species in warm temperate to subtropical regions worldwide. Climate change poses significant challenges to agriculture, particularly through drought and heat stress, which adversely affect ryegrass yield and may be further exacerbated by global warming. Despite numerous research achievements in recent years, a comprehensive bibliometric analysis of the literature on drought and heat stress in perennial ryegrass is lacking. This study provides a quantitative analysis of relevant literature published from 1994 to 2024, utilizing the Web of Science database to evaluate global research trends and priorities. The results indicate a consistent annual growth in publication output, with China and the United States being major contributors, and the journal Crop Science publishing the most papers. Keyword analysis shows that “growth,” “endophytic fungi,” and “yield” are most frequently used in drought stress research, while “growth,” “gene,” and “leaf” are common in heat stress research. Over the past 30 years, research has mainly focused on phenotype, response mechanisms, and drought and heat resistance techniques in perennial ryegrass. Endophyte have become a hot topic in drought stress research in recent years and have also gained attention in heat stress research, suggesting future research directions in this area. Furthermore, there is a need to strengthen research on the molecular mechanisms associated with drought stress in ryegrass, as well as to explore molecular responses to heat stress. The research trend shows increasing attention to the interaction between drought and heat stress, indicating it will become an important direction for future studies. The findings of this study offer valuable insights for guiding future research on perennial ryegrass under drought and heat stress conditions and provide useful information for researchers in related fields.

Loss of Sult1a1 reduces body weight and increases browning of white adipose tissue

Background and objectiveOverweight and obesity affects millions of individuals worldwide and consequently represents a major public health concern. Individuals living with overweight and obesity have difficulty maintaining a low body weight due to known physiological mechanisms which prevent further weight loss and drive weight regain. In contrast, mechanisms which promote low body weight maintenance receive less attention and are largely unknown. To uncover these intrinsic mechanisms, we investigated a human cohort of constitutionally thin (CT) individuals which maintain a low body weight and are resistant to weight gain despite exposure to an obesogenic environment.MethodsTo identify novel genes that contribute to low body weight maintenance, we performed transcriptomics on adipose tissue biopsies collected from CT and normal body weight (NBW) individuals and identified sulfotransferase 1A1 (SULT1A1) as a target for further investigation in mice. Sult1a1 knockout (KO) mice were fed a standard diet to assess the impact of Sult1a1 deletion on metabolic traits. To determine if high-fat feeding recapitulated the CT weight gain resistance phenotype, Sult1a1 KO mice were fed a high-fat diet for 13-weeks. A subset of wild-type and Sult1a1 KO mice from the standard diet were further analyzed for characterization of adipose tissue respiratory capacity.ResultsIn comparison to NBW controls, adipose tissue from CT individuals expresses less SULT1A1. Sult1a1 KO mice weigh 10% less at the end of the study period and on a high-fat diet, Sult1a1 KO mice tended to gain less weight and had reduced fat mass at 14-weeks of age. These changes were associated with reduced fasting insulin and lessened adipose tissue inflammation and fibrosis. Subcutaneous adipose tissue from Sult1a1 KO mice on a standard chow diet had elevated leak respiration, uncoupling protein 1 (UCP1) expression and increased expression of a mitochondrial marker, VDAC, associating Sult1a1 deletion to adipose tissue browning.ConclusionsOur results associate Sult1a1 deletion with a tendency for lower body weight through remodeling of white adipose tissue towards a brown phenotype. The presence of UCP1, the expression of an additional mitochondrial protein and increased respiratory capacity suggest browning of the subcutaneous adipose tissue depot of Sult1a1 KO mice.

Polyploidy confers better cold tolerance in Daphnia

Despite decades of studies on the differential distribution of polyploid organisms, the causes of this pattern have yet to be elucidated. This study aimed to explore some of the possible physiological mechanisms explaining the differential northern distribution of polyploid clones of Daphnia pulex compared to the one of the diploid parental species. The critical thermal minimum (CTmin) was measured in 17 D. pulex clones of contrasted ploidy (diploid and triploid) and geographic origins (temperate and subarctic climates) reared under low and high temperatures (16 and 24°C). Triploid clones had better cold tolerance (lower CTmin) than both sympatric and temperate diploid clones. No significant association was found between CTmin and body size nor with cell size. We suggest that triploids might express a cold shock resistant phenotype related to higher gene expression and/or fatty acid profiles. Cold tolerance can be viewed as one of the possible reasons for polyploid preponderance in subarctic climates.

Impact of COVID-19 pandemic on antimicrobial resistance of Proteus mirabilis in a Brazilian hospital.

This study analyzes the resistance and virulence profiles of Proteus mirabilis isolates obtained from patients admitted to the University Hospital of Londrina, Paraná, between 2019 and 2022. We evaluated the antimicrobial resistance phenotypes, genes associated with resistance, biofilm formation through a phenotypic assay, and the presence of specific virulence genes. When comparing the "pre-pandemic" (2019) and "pandemic" (2020-2022) periods, we observed an increase in resistance rates to all tested antimicrobials. Multidrug-resistant (MDR) pathogens producing extended-spectrum β-lactamase (ESBL) phenotypes were isolated in both periods, but their occurrence was significantly higher during the pandemic. We also observed an increase in the frequency of nearly all studied resistance genes. The virulence profiles remained largely unchanged. Analysis of patients' clinical and demographic data revealed that those hospitalized during the pandemic were older, required longer hospital stays, and had a higher usage of invasive devices. These findings suggest that the recent COVID-19 pandemic has impacted the antimicrobial resistance of P. mirabilis, a bacterium of significant clinical interest associated with urinary tract infections (UTIs) and healthcare-associated infections (HAIs).

Geography, Antimicrobial Resistance, and Genomics of Salmonella enterica (Serotypes Newport and Anatum) from Meat in Mexico (2021–2023)

Salmonella enterica non-typhoidal is a major contributor to diarrheal diseases, with over 2600 serovars identified across diverse environments. In Mexico, serovars Newport and Anatum have shown a marked increase, especially in foodborne disease, posing a public health problem. We conducted a cross-sectional study from 2021 to 2023 using active epidemiological surveillance to assess contamination in ground beef and pork at butcher shops nationwide. It involved isolation, phenotypic antimicrobial resistance, comparative genomics, spatial distribution, antimicrobial-resistance genes, and pangenome analysis. A total of 402 non-typhoidal S. enterica strains were isolated, including 59 Newport and 50 Anatum. After curating for redundancy, 45 Newport and 32 Anatum strains remained. We found that 75% of Newport strains exhibited multidrug resistance (MDR), compared to 25% of Anatum strains. Salmonella Newport also showed a broader distribution and stronger antibiotic-resistance capacity, particularly due to genes such as mphA and ramA. Our pangenome analysis showed a predominance of cell maintenance and survival-process genes in the accessory genome of both serotypes. Considering unique genes, Salmonella Anatum and Newport showed a notorious abundance of genes with functions related to replication, recombination, and repair. The substantial rise of Anatum and Newport strains in meat samples for human consumption presents an epidemiological alert, highlighting the critical need for stringent surveillance programs to mitigate human and ecosystem health risks.

Investigating the stability of phenotype, seed components and powdery mildew resistance of the &lt;i&gt;GmMLO&lt;/i&gt; edited soybean plants

Previously, utilizing the CRISPR/Cas9 system, we had successfully induced targeted mutations in the GmMLO genes of the Vietnamese elite soybean cultivar ĐT26 for the first time. The mutant lines carried homozygous mutations of four or three GmMLO genes (including GmMLO02, GmMLO19, GmMLO23 and/or GmMLO20) with no pleiotrophic effects and increased powdery mildew resistance in the T3 generation. In this study, we selected two representative lines and evaluated them in the T4 generation to see if their phenotype and resistance were maintained stably. The analysis results of agronomic and yield parameters under the net-house conditions indicated that there were no undesired data in the two mutant lines in comparison with the wild-type. In addition, the major nutritional compositions of the seeds including the fatty acids, free amino acids and crude protein content of the mutant lines were similar to the control line. Importantly, the response to Erysiphe diffusa challenge of the quadruple mutant line was still maintained at a moderate resistance level (grade 2.5) as compared to the moderate infection level of the wild-type and the triple mutant line (approximately grade 4). These results again demonstrate that inducing targeted mutations of four tested GmMLO genes via the CRISPR/Cas9 system is not accompanied with undesired traits, and the quadruple mutant line is the potential one with increased powdery mildew resistance maintained stably through generations. This soybean mutant line will be valuable material for further breeding programs as well as being able to be propagated for production.

Prevalence of Mobile Colistin Resistance (&lt;i&gt;mcr&lt;/i&gt;) Genes in &lt;i&gt;Acinetobacter baumannii&lt;/i&gt;: Isolates of Clinical Infection from an Iranian University Hospital

Background: The emergence of colistin resistance is a global issue that threatens the effectiveness of colistin treatment against multidrug-resistant Gram-negative bacteria. Objectives: The present study reports on the prevalence of colistin resistance and mcr-encoding genes in Acinetobacter baumannii strains isolated from patients referred to Shahid Rahimi Hospital, Khorramabad, Iran, from January to August 2019. Methods: A total of 47 non-duplicate A. baumannii isolates were obtained from clinical specimens of patients. Colistin susceptibility of the isolates was assessed using the broth microdilution method, and the presence of mcr-encoding genes was determined through the use of PCR. Results: Out of the total 47 isolates belonging to A. baumannii, 14 isolates (29.8%) were resistant to colistin. The minimum inhibitory concentration (MIC) of colistin ranged from 2 to 256 μg/mL, and the MIC50 and MIC90 values for colistin were 0.25 μg/mL and 16 μg/mL, respectively. The presence of mcr-1 and mcr-2 was detected in 6 (12.7%) and 2 (4%) isolates, respectively. However, no isolates harbored the mcr-3 gene. Except for one isolate, none of the mcr-positive isolates exhibited phenotypic resistance to colistin. Conclusions: The higher phenotypic prevalence of colistin resistance compared to genotypic characterization, along with the discrepancy with the presence of mcr genes, suggests the need to monitor and consider all molecular mechanisms of colistin resistance as a last-resort treatment option.

CEA-Induced PI3K/AKT Pathway Activation through the Binding of CEA to KRT1 Contributes to Oxaliplatin Resistance in Gastric Cancer

BackgroundThe serum level of carcinoembryonic antigen (CEA) has prognostic value in patients with gastric cancer (GC) receiving oxaliplatin-based chemotherapy. As the molecular functions of CEA are increasingly uncovered, its role in regulating oxaliplatin resistance in GC attracts attention. MethodsThe survival analysis adopted the KaplanMeier method. Effects of CEA on proliferative capacity were investigated using CCK8, colony formation, and xenograft assays. Oxaliplatin sensitivity was identified through IC50 detection, apoptosis analysis, comet assay, organoid culture model, and xenograft assay. Multi-omics approaches were utilized to explore CEA’s downstream effects. The binding of CEA to KRT1 was confirmed through proteomic analysis and Co-IP, GST pull-down, and immunofluorescence colocalization assays. Furthermore, small molecule inhibitors were identified using virtual screening and surface plasmon resonance. ResultsStarting from clinical data, we confirmed that CEA demonstrated superior ability to predict the prognosis of patients with GC who received oxaliplatin-based chemotherapy, particularly in predicting recurrence-free survival based on serum CEA level. In vitro and in vivo experiments revealed CEAhigh GC cells presented increased proliferative capacity and decreased oxaliplatin sensitivity. The resistance phenotype was transmitted through secreted CEA. Multi-omics analysis revealed that CEA activated the PI3K/AKT pathway by binding to KRT1, leading to oxaliplatin resistance. Finally, the small molecule inhibitor evacetrapib, which competitively inhibits the CEA-KRT1 interaction, was identified and validated in vitro. ConclusionsIn summary, the CEA-KRT1-PI3K/AKT axis regulates oxaliplatin sensitivity in GC cells. Treatment with small molecule inhibitors such as evacetrapib to inhibit this interaction constitutes a novel therapeutic strategy.

Role and mechanism of the outer membrane porin LamB in T-2 mycotoxin-mediated extensive drug resistance in Escherichia coli

The influence of mycotoxins in ecological niches shared with antibiotic-resistant bacteria (ARB) remains underexplored. This study examined the impact of T-2 mycotoxin on the evolution of antibiotic resistance in Escherichia coli, highlighting the role of specific porins. Our findings revealed that exposure to 10ng/mL of T-2 toxin induced multi-drug resistant (MDR) phenotypes in three E. coli. At 10-5ng/mL, T-2 toxin caused E. coli ATCC 25922 to develop stable resistance to 13 critical antibiotics, with minimum inhibitory concentrations (MICs) increasing 16- to several thousand-fold. This resistance was linked to the downregulation of the mal gene cluster. Notably, T-2 toxin reduced membrane permeability by downregulating lamB, facilitating its own entry and reducing the intracellular accumulation of both the toxin and antibiotics, thereby enhancing resistance development. LamB mediated the XDR phenotypes in E. coli, particularly by blocking last-resort antibiotics such as cephalosporins, carbapenems, tigecycline, and colistin, complicating treatment strategies. LamB demonstrated high binding affinities for T-2 toxin and various antibiotics, with specific binding sites identified for meropenem (Arg134), imipenem (Ser148, Arg170, Lys129), ceftazidime (Phe106, Lys129), and cefepime (Tyr66, Gln267, Lys269), exhibiting binding energies of -2.93, -2.58, -2.53, and -4.3, respectively. These findings suggest that even low levels of T-2 mycotoxin pose a substantial public health risk. They underscore the urgent need to address these contaminants and open new avenues for antibiotic resistance research.

Predicting antimicrobial resistance in E. coli with discriminative position fused deep learning classifier

Escherichia coli (E. coli) has become a particular concern due to the increasing incidence of antimicrobial resistance (AMR) observed worldwide. Using machine learning (ML) to predict E. coli AMR is a more efficient method than traditional laboratory testing. However, further improvement in the predictive performance of existing models remains challenging. In this study, we collected 1,937 high-quality whole genome sequencing (WGS) data from public databases with an antimicrobial resistance phenotype and modified the existing workflow by adding an attention mechanism to enable the modified workflow to focus more on core single nucleotide polymorphisms (SNPs) that may significantly lead to the development of AMR in E. coli. While comparing the model performance before and after adding the attention mechanism, we also performed a cross-comparison among the published models using random forest (RF), support vector machine (SVM), logistic regression (LR), and convolutional neural network (CNN). Our study demonstrates that the discriminative positional colors of Chaos Game Representation (CGR) images can selectively influence and highlight genome regions without prior knowledge, enhancing prediction accuracy. Furthermore, we developed an online tool (https://github.com/tjiaa/E.coli-ML/tree/main) for assisting clinicians in the rapid prediction of the AMR phenotype of E. coli and accelerating clinical decision-making.

Benzimidazole Resistance-Associated Mutations in the β-tubulin Gene of Hookworms: A Systematic Review.

There is a growing number of reports on the occurrence of benzimidazole resistance-associated single nucleotide polymorphisms (SNPs) in the β-tubulin isotype 1 gene of various helminths of veterinary, and public health concerns. However, a comprehensive analysis of their occurrence, and their contributions to conferring benzimidazole resistance among hookworms has yet to be done. The objectives of this systematic review are to summarize and synthesize peer-reviewed evidence on the occurrence of these resistance-associated mutations in hookworms, document their geographical distribution, and assess their contributions to conferring phenotypic resistance. Three databases were systematically searched using specific keywords. Research that assessed the occurrence of benzimidazole resistance-associated SNPs in hookworms, papers that reported the geographical distribution of these SNPs, and studies that investigated the SNPs' resistance-associated phenotypic effects were included in the review. Research that was not done in hookworms, papers not in the English language, and literature reviews and book chapters were excluded. Critical appraisal checklists were used to determine the risk of bias in the selected papers. Data were extracted from the selected studies and analyzed. PROSPERO Systematic Review Protocol Registration No.: CRD42024510924. A total of 29 studies were included and analyzed. Of these, four were conducted in a laboratory setting, eight described the development and validation of SNP detection methods, and the remaining 17 involved field research. Seven SNP-induced amino acid substitutions at four loci were reported among several hookworm species: Q134H, F167Y, E198A, E198K, E198V, F200Y, and F200L. SNPs have been reported in isolates occurring in the United States, Canada, Brazil, Haiti, Australia, New Zealand, Kenya, Ghana, Mozambique, and Tanzania. Resistance mutations have not been reported in Asia. E198A and F200L were reported in Ancylostoma ceylanicum with laboratory-induced resistance. F167Y and Q134H conferred resistance in A. caninum, as revealed by in vitro investigations and field assessments. There is insufficient peer-reviewed evidence to prove the association between SNP occurrence and resistance. Mutations in the β-tubulin isotype 1 gene confer benzimidazole resistance in A. caninum and A. ceylanicum, but similar evidence is lacking for other human hookworms. Understanding benzimidazole resistance through further research can better inform treatment, prevention, and control strategies.

Site-selective modifications by lipid A phosphoethanolamine transferases linked to colistin resistance and bacterial fitness.

Rising levels of resistance to increasing numbers of antimicrobials have led to the revival of last resort antibiotic colistin. Unfortunately, resistance to colistin is also spreading in the form of mcr genes, making it essential to (i) improve the identification of resistant bacteria to allow clinicians to prescribe effective drug regimens and (ii) develop new combination therapies effective at targeting resistant bacteria. Our results demonstrate that PETs, including MCR variants, are site-selective in Escherichia coli and that site-selectivity correlates with the level of susceptibility and fitness costs conferred by certain PETs. Site selectivity associated with a given PET may not only help predict colistin resistance phenotypes but may also provide an avenue to (i) improve drug regimens and (ii) develop new combination therapies to better combat colistin-resistant bacteria.

Antibiotic resistance genotype, phenotype, and clinical outcomes in patients with Gram-negative infections at Rabin Medical Center in Israel.

While there have been several studies that attempt to find clinical predictors of outcomes in patients hospitalized with bacterial infections, less has been done to combine clinical data with genomic mechanisms of antibiotic resistance. This study focused on a hospitalized patient population in Israel with infections due to medically important bacterial pathogens as a way to build a framework that would unite clinical data with both bacterial antibiotic susceptibility and genomic data. Merging both clinical and genomic data allowed us to find both bacterial and clinical factors that impact certain clinical outcomes. As genome sequencing of bacteria becomes both rapid and commonplace, near real-time monitoring of resistance determinants could help to optimize clinical care and potentially improve outcomes in these patients.

First Detection of Vibrio parahaemolyticus in Migratory Birds in Egypt: Antibiogram, Virulence, and Resistance Gene Profiles Indicating Zoonotic and Public Health Risks.

This study examined the occurrence of Vibrio parahaemolyticus obtained from migrating birds, marking the first instance of such research conducted in Egypt. The study assessed potential risks using an antibiogram, virulence characteristics, antibiotic-resistance, and gene profile. Randomly collected 80 samples were tested for V. parahaemolyticus. Eleven (13.75%) samples were V. parahaemolyticus-contaminated. All isolates were positive for 16SrRNA and species-specific toxR genes. Interestingly, our strain is genetically similar to human and shrimp isolates, suggesting zoonotic transmission may pose a health danger. All isolates had 100% l-lysine decarboxylase, 45.45% beta-hemolytic, and 100% l-ornithine decarboxylase activity. All isolates displayednol-arginine decarboxylase activity. Notably, every isolate possessed a minimum of two virulence genes. In addition, the profiles of virulence genes were identified, tdh + /trh + (27.3%), tdh-/trh + (27.3%), and tdh + /trh- (45.4%). Out of the V. parahaemolyticus isolates, 18.2% (2/11) were extensively drug-resistant (XDR) to six different antimicrobials classes and possessed the blaTEM, blaOXA, sul1, and tetA genes. Furthermore, 63.6% of the isolates displayed multidrug resistance (MDR). The correlation highlights a strong relationship between phenotypic and genotypic resistance. Besides thestrong correlation between virulence and resistance genes.In summary, this work highlighted the presence of newly identified MDR and XDR V. parahaemolyticus carried toxR, trh, and tdh virulence genes, as well as blaTEM, blaOXA, sul1, and tetA resistance genes in migratory birds, indicating a significant public health risk.

Insights into antibiotic resistance promoted by quinolone exposure.

Quinolone-induced antibiotic resistance (QIAR) refers to the phenomenon by which bacteria exposed to sublethal levels of quinolones acquire resistance to non-quinolone antibiotics. We have explored this in Escherichia coli MG1655 using a variety of compounds and bacteria carrying a quinolone-resistance mutation in gyrase, mutations affecting the SOS response, and mutations in error-prone polymerases. The nature of the antibiotic-resistance mutations was determined by whole-genome sequencing. Exposure to low levels of most quinolones tested led to mutations conferring resistance to chloramphenicol, ampicillin, kanamycin, and tetracycline. The mutations included point mutations and deletions and could mostly be correlated with the resistance phenotype. QIAR depended upon DNA gyrase and involved the SOS response but was not dependent on error-prone polymerases. Only moxifloxacin, among the quinolones tested, did not display a significant QIAR effect. We speculate that the lack of QIAR with moxifloxacin may be attributable to it acting via a different mechanism. In addition to the concerns about antimicrobial resistance to quinolones and other compounds, QIAR presents an additional challenge in relation to the usage of quinolone antibacterials.