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Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts. [ABSTRACT FROM AUTHOR]

Tuberculosis remains a formidable global health challenge, with drug-resistant strains posing significant hurdles in its eradication efforts. Addressing the challenge of drug-resistant and multidrug-resistant tuberculosis requires a multifaceted approach encompassing enhanced diagnostics, novel therapeutics, and patient-centered care models. This study aims to find the treatment outcomes of DR-TB patients registered at tertiary care settings along estimation of impact of associated adverse events. This retrospective study was undertaken at a tertiary care setting of Lahore Punjab Pakistan during the year 2023. Using a predefined scheme of variables data was collected Regression analysis was applied by taking death and treatment failure as adverse outcomes excluding the treatment defaulter patients as their final fate was not known. A total of 1438 drug resistant TB patients comprising of 49.4% males and 50.6 females with mean age of patients at the time of registration as 35.08±15.91 years were included in final analysis. A high number of 17.4% patients were died, 56.2% patients were cured and 10.4% successfully completed their treatment. Rate of loss to follow up was noted to be 11.1% and treatment failure were 4.9% in this study. Regression model showed that patients aged =34 years, patients having previous history of treatment and treatment strategy other than LTR are at greater risk of adverse events. Overall success rate of treatment remained to be 66.6% remained far below of the target laid down by the WHO. A high mortality rate was found to be associated with drug resistant tuberculosis patients. Age =34 years, prior history of TB treatment and treatment strategy are risk factors for death of DR TB patients. [ABSTRACT FROM AUTHOR]

Jingnan Zhao,1 Chengyu Qian,2 Youqiao Jiang,1,3 Wangrui He,1 Wenhua Wu1 1Tuberculosis Control Department, Jiangxi Provincial Center for Disease Control and Prevention, Nanchang, 330029, People’s Republic of China; 2Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China; 3Young Scientific Research and Innovation Team, Jiangxi Provincial Center for Disease Control and Prevention, Nanchang, Jiangxi, 330029, People’s Republic of ChinaCorrespondence: Wangrui He, Tuberculosis Control Department, Jiangxi Provincial Center for Disease Control and Prevention, No. 555, Beijing East Road, Nanchang, Jiangxi, 330029, People’s Republic of China, Email jxcdccbs@126.comPurpose: In this study, we aimed to determine the transmission pattern of multidrug-resistant tuberculosis (MDR-TB) isolates circulating in Jiangxi Province with whole-genome sequencing (WGS). In addition, we also sought to describe mutational resistome of MDR-TB isolates.Patients and Methods: A total of 115 MDR-TB isolates determined by the phenotypic proportion method of drug susceptibility testing between January 2018 and December 2022 from provincial drug surveillance (DRS) in Jiangxi were included in our analysis. The demographic data and treatment history were extracted from the National TB Registry System. WGS was used to analyze the genotypic characteristics of drug resistance and transmissions.Results: About 62.6% of MDR-TB strains were isolated from cases that received previous anti-tuberculosis treatment. According to the WGS results, 96.5% were genotypic MDR-TB, and more than half of MDR-TB isolates tested were also resistant to streptomycin (59.1%), ethambutol (56.5%), and fluroquinolones (53.0%), while resistance to cycloserine and linezolid was lowest, only in two (1.7%) and one (0.9%) isolate, respectively. Ser450Leu in rpoB (57.9%), Ser315Thr in katG (74.1%), Met306Val in embB (40.0%), Lys43Arg in rpsL (75.0%), Ala90Val in gyrA (32.8%) were predominant mutant types among the rifampin-, isoniazid-, ethambutol-, streptomycin-, fluoroquinolones-resistant isolates, respectively. Lineage 2 (East Asian genotype) occurred at the highest frequency with 97 cases (84.3%), followed by lineage 4 (Euro-American genotype) with 18 cases (15.7%). Additionally, 5 clusters consisting of 10 isolates were identified in the present study, demonstrating a clustering rate of 8.7%.Conclusion: MDR/Rifampicin-Resistant (RR)-TB epidemic in this region is driven by lineage 2 clade that also show higher resistance to other anti-tuberculosis drugs. Lower cluster rates compared with a relatively higher proportion of new MDR-TB cases indicate that a considerable number of MDR-TB cases remain undiagnosed.Keywords: Mycobacterium tuberculosis, drug resistant, whole-genome sequencing, genetic diversity, transmission dynamics

Abstract Background Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. Methods We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). Results After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p

In this study, 858 novel long non-coding RNAs (lncRNAs) were predicted as sensitive and resistant strains of Haemonchus contortus to ivermectin. These lncRNAs underwent bioinformatic analysis. In total, 205 lncRNAs significantly differed using log2 (difference multiplicity) > 1 or log2 (difference multiplicity) < − 1 and FDR < 0.05 as the threshold for significant difference analysis. We selected five lncRNAs based on significant differences in expression, cis-regulation, and their association with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. These expressions of lncRNAs, namely MSTRG.12610.1, MSTRG.8169.1, MSTRG.6355.1, MSTRG.980.1, and MSTRG.9045.1, were significantly downregulated. These findings were consistent with the results of transcriptomic sequencing. We further investigated the relative expression of target gene mRNAs and the regulation of mRNA and miRNA, starting with lncRNA cis-regulation of mRNA, and constructed a lncRNA-mRNA-miRNA network regulation. After a series of statistical analyses, we finally screened out UGT8, Unc-116, Fer-related kinase-1, GGPP synthase 1, and sart3, which may be involved in developing drug resistance under the regulation of their corresponding lncRNAs. The findings of this study provide a novel direction for future studies on drug resistance targets. [ABSTRACT FROM AUTHOR]

GeneXpert MTB/RIF is a rapid molecular diagnostic tool capable of simultaneously detecting Mycobacterium tuberculosis and rifampicin resistance. This study aimed to assess the diagnostic precision of GeneXpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and evaluate the performance for detecting of rifampicin resistance. Of 37,695 samples, 7156 (18.98%) were tuberculosis-positive, and 509 (7.11%) were rifampicin-resistant. The sensitivity, specificity, positive predictive value, negative predictive value, disease prevalence, and accuracy of the GeneXpert MTB/RIF assay for pulmonary tuberculosis were 99.87% (95%CI: 99.75–99.94), 99.92% (95%CI: 99.88–99.95), 99.71% (95%CI: 99.54–99.82), 99.97% (95%CI: 99.93–99.98), 21.38% (95%CI: 20.92–21.86), and 99.91% (95%CI: 99.87–99.94), respectively. For extrapulmonary tuberculosis, the sensitivity, specificity, PPV, NPV, disease prevalence, and accuracy of GeneXpert MTB/RIF assay accounted for 99.45% (95%CI: 98.73–99.82), 99.84% (95%CI: 99.73–99.92), 98.70% (95%CI: 97.73–99.25), 99.93% (95%CI: 99.84–99.97), 10.64% (95%CI: 9.99–11.31), and 99.80% (95%CI: 99.68–99.88), respectively. Despite its high sensitivity for detecting tuberculosis and rifampicin resistance, GeneXpert MTB/RIF had contradictory results for 20.5% of cases among patients with smear-negative results and 54.9% of cases among patients with a high risk of multidrug-resistant tuberculosis. Of 46% fluoroquinolone-resistant cases, 16.56% (26/157) were multidrug-resistant tuberculosis isolates, and 4.02% (20/498) were isoniazid-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone-resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Further, our study indicated that increased fluoroquinolone resistance among rifampicin-resistant and isoniazid-resistant tuberculosis endangers the success of newly endorsed MDR-TB regimens. [ABSTRACT FROM AUTHOR]

Drug resistance substantially compromises antibiotic therapy and poses a serious threat to public health. Fusidic acid (FA) is commonly used to treat staphylococcal infections, such as pneumonia, osteomyelitis and skin infections. However, Gram-negative bacteria have natural resistance to FA, which is almost restrained in cell membranes due to the strong interactions between FA and phospholipids. Herein, we aim to utilize the strong FA–phospholipid interaction to pre-form a complex of FA with the exogenous phospholipid. The FA, in the form of an FA–phospholipid complex (FA-PC), no longer interacts with the endogenous membrane phospholipids and thus can be delivered into bacteria cells successfully. We found that the water solubility of FA (5 µg/mL) was improved to 133 µg/mL by forming the FA-PC (molar ratio 1:1). Furthermore, upon incubation for 6 h, the FA-PC (20 µg/mL) caused a 99.9% viability loss of E. coli and 99.1% loss of P. aeruginosa, while free FA did not work. The morphology of the elongated bacteria cells after treatment with the FA-PC was demonstrated by SEM. The successful intracellular delivery was shown by confocal laser scanning microscopy in the form of coumarin 6-PC (C6-PC), where C6 served as a fluorescent probe. Interestingly, the antibacterial effect of the FA-PC was significantly compromised by adding extra phospholipid in the medium, indicating that there may be a phospholipid-based transmembrane transport mechanism underlying the intracellular delivery of the FA-PC. This is the first report regarding FA-PC formation and its successful reversing of Gram-negative bacteria resistance to FA, and it provides a platform to reverse transmembrane delivery-related drug resistance. The ready availability of phospholipid and the simple preparation allow it to have great potential for clinical use. [ABSTRACT FROM AUTHOR]

Abstract Background Epilepsy contributes to high morbidity among children and adolescents in developing countries. A quarter of all children with epilepsy will be resistant to anti-seizure medications (ASMs), with associated neurocognitive impairments and risk of higher mortality. This study aimed to estimate and characterize drug-resistant epilepsy (DRE) (defined as failure to achieve sustained remission after adequate trials of two tolerated and appropriately chosen ASMs) and its associated factors among children and adolescents with epilepsies attending the pediatric neurology clinic at Muhimbili National Hospital (MNH), Dar es Salaam Tanzania. Methods This cross-sectional study was conducted from June 2020 to June 2021. Children with epilepsies and who had been treated with ASMs for at least 3 months were eligible for inclusion. Exclusion criteria included children whose caregivers denied consent and those who exhibited acute medical conditions necessitating admission on the scheduled visit day. Data on demographic characteristics, perinatal history, detailed history of the seizures semiology, drug history, magnetic resonance imaging (MRI), and electroencephalography (EEG) results were obtained from caregivers and medical records available during recruitment. Seizures and epilepsies were classified using the 2017 International League Against Epilepsy (ILAE) classification. Logistic regression was used to determine factors associated with DRE. Results A total of 236 children and adolescents aged between 4 months and 15 years (Median age 72 months (IQR = 42–78)) were enrolled in this study. We found the proportion of DRE to be 14.8% in this cohort. Of the thirty-five patients with DRE, 60% had generalized epilepsy and almost 25% had a diagnosis of an epilepsy syndrome, the most common being Lennox-Gastaut syndrome (LGS). Structural abnormalities on brain MRI were seen in almost 80% of all patients with DRE, the most prevalent being cystic encephalomalacia, which was observed in 34% of patients. Patients using both ASMs and alternative therapies accounted for 9% of this cohort. The onset of seizures during the first month of life (aOR = 1.99; 95%CI 1.7–4.6; p = 0.031) and high initial seizure frequency (aOR = 3.6; 95%CI 1.6-8;p = 0.002) were found to be independently associated with DRE. Conclusion The proportion of DRE in Tanzania is high. Patients with neonatal onset seizures and high initial seizure frequency should be followed up closely to ensure early diagnosis of DRE.

GeneXpert MTB/RIF is a rapid molecular diagnostic tool capable of simultaneously detecting Mycobacterium tuberculosis and rifampicin resistance. This study aimed to assess the diagnostic precision of GeneXpert MTB/RIF assay to detect pulmonary and extrapulmonary tuberculosis and evaluate the performance for detecting of rifampicin resistance. Of 37,695 samples, 7156 (18.98%) were tuberculosis-positive, and 509 (7.11%) were rifampicin-resistant. The sensitivity, specificity, positive predictive value, negative predictive value, disease prevalence, and accuracy of the GeneXpert MTB/RIF assay for pulmonary tuberculosis were 99.87% (95%CI: 99.75–99.94), 99.92% (95%CI: 99.88–99.95), 99.71% (95%CI: 99.54–99.82), 99.97% (95%CI: 99.93–99.98), 21.38% (95%CI: 20.92–21.86), and 99.91% (95%CI: 99.87–99.94), respectively. For extrapulmonary tuberculosis, the sensitivity, specificity, PPV, NPV, disease prevalence, and accuracy of GeneXpert MTB/RIF assay accounted for 99.45% (95%CI: 98.73–99.82), 99.84% (95%CI: 99.73–99.92), 98.70% (95%CI: 97.73–99.25), 99.93% (95%CI: 99.84–99.97), 10.64% (95%CI: 9.99–11.31), and 99.80% (95%CI: 99.68–99.88), respectively. Despite its high sensitivity for detecting tuberculosis and rifampicin resistance, GeneXpert MTB/RIF had contradictory results for 20.5% of cases among patients with smear-negative results and 54.9% of cases among patients with a high risk of multidrug-resistant tuberculosis. Of 46% fluoroquinolone-resistant cases, 16.56% (26/157) were multidrug-resistant tuberculosis isolates, and 4.02% (20/498) were isoniazid-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone-resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Further, our study indicated that increased fluoroquinolone resistance among rifampicin-resistant and isoniazid-resistant tuberculosis endangers the success of newly endorsed MDR-TB regimens.

Avian trichomoniasis, caused by the protozoan parasite Trichomonas gallinae, is a prevalent and economically significant disease in pigeons. This study investigated the drug resistance of T. gallinae isolates in Guangdong Province, China. The results revealed that 25.3% (20/79) of the isolates were resistant to one or more of the four nitroimidazole drugs tested, namely, metronidazole, dimetridazole, secnidazole, and tinidazole. Secnidazole elicited the highest resistance rate (19.0%; 15/79), followed by tinidazole (17.7%; 14/79), metronidazole (17.7%; 14/79), and dimetridazole (13.9%; 11/79). An enormous majority of the resistant isolates (70.0%; 14/20) exhibited resistance to multiple drugs. Additionally, the resistance rate was significantly higher in isolates from birds aged < 30 days (53.3%; 8/15) than in those from older birds (23.1%; 12/52). Moreover, no drug resistance was detected in female pigeons. The genotype of the isolated strain was also associated with drug resistance. Specifically, 50.0% (15/30) of ITS-B genotypes exhibited resistance to drugs, while only 10.2% (5/49) of ITS-A genotypes demonstrated resistance. This study also found the growth characteristics of different Trichomonas isolates to be influenced by their genotypes and initial inoculum concentrations. These findings underscore the urgent need for effective measures to control and prevent drug-resistant T. gallinae infections in pigeons, thus ensuring the stable development of the pigeon industry. [ABSTRACT FROM AUTHOR]

Background: Epilepsy contributes to high morbidity among children and adolescents in developing countries. A quarter of all children with epilepsy will be resistant to anti-seizure medications (ASMs), with associated neurocognitive impairments and risk of higher mortality. This study aimed to estimate and characterize drug-resistant epilepsy (DRE) (defined as failure to achieve sustained remission after adequate trials of two tolerated and appropriately chosen ASMs) and its associated factors among children and adolescents with epilepsies attending the pediatric neurology clinic at Muhimbili National Hospital (MNH), Dar es Salaam Tanzania. Methods: This cross-sectional study was conducted from June 2020 to June 2021. Children with epilepsies and who had been treated with ASMs for at least 3 months were eligible for inclusion. Exclusion criteria included children whose caregivers denied consent and those who exhibited acute medical conditions necessitating admission on the scheduled visit day. Data on demographic characteristics, perinatal history, detailed history of the seizures semiology, drug history, magnetic resonance imaging (MRI), and electroencephalography (EEG) results were obtained from caregivers and medical records available during recruitment. Seizures and epilepsies were classified using the 2017 International League Against Epilepsy (ILAE) classification. Logistic regression was used to determine factors associated with DRE. Results: A total of 236 children and adolescents aged between 4 months and 15 years (Median age 72 months (IQR = 42–78)) were enrolled in this study. We found the proportion of DRE to be 14.8% in this cohort. Of the thirty-five patients with DRE, 60% had generalized epilepsy and almost 25% had a diagnosis of an epilepsy syndrome, the most common being Lennox-Gastaut syndrome (LGS). Structural abnormalities on brain MRI were seen in almost 80% of all patients with DRE, the most prevalent being cystic encephalomalacia, which was observed in 34% of patients. Patients using both ASMs and alternative therapies accounted for 9% of this cohort. The onset of seizures during the first month of life (aOR = 1.99; 95%CI 1.7–4.6; p = 0.031) and high initial seizure frequency (aOR = 3.6; 95%CI 1.6-8;p = 0.002) were found to be independently associated with DRE. Conclusion: The proportion of DRE in Tanzania is high. Patients with neonatal onset seizures and high initial seizure frequency should be followed up closely to ensure early diagnosis of DRE. [ABSTRACT FROM AUTHOR]

The primary goal of this work was to develop a cost-effective, non-toxic, eco-friendly, and simple approach for the green synthesis of CoFe2O4 nanoparticles (NPs) using Aloe vera leaf extract by the sol–gel auto-combustion method. In order to figure out their structural, morphological, and magnetic properties, the synthesized NPs were characterized using X-ray diffraction (XRD), Fourier transform infrared (FTIR), scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscope (TEM), dynamic light scattering (DLS), zeta potential, and vibrating-sample magnetometer (VSM). XRD analysis showed that particles had a single-phase spinel crystalline structure with an average crystalline size of 33.5 nm. Under VSM studies, the produced NPs exhibit a soft ferromagnetic property. SEM revealed that the as-prepared NPs were agglomerated due to their magnetic behavior. To the best of our knowledge, the anticandidal, antibiofilm, antibacterial, and anticancer activities of CoFe2O4 NPs toward drug-resistant gram-positive and gram-negative bacteria, as well as fungal strains, have been comprehensively investigated for the first time. The synthesized NPs had a minimal inhibitory concentration of 0.25–0.75 mg/ml against the tested pathogens. CoFe2O4 NPs inhibited the biofilm formation by 37.3–61.8% in selected strains at concentrations of 0.125–0.5 mg/ml. It was observed that the NPs not only suppress biofilm formation but also eradicate established mature biofilms by 50.9–64.49% that was further supported by SEM. SEM analysis shows that NPs significantly inhibit the colonization and aggregation of tested biofilm strains. Light microscopic analysis revealed that NPs completely inhibit the development of hyphae and filaments in Candida albicans, which significantly attenuates their pathogenicity. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and 4′,6-diamidino-2-phenylindole (DAPI) staining demonstrate that NPs significantly inhibit the proliferation of HCT-116 and HeLa cells. Furthermore, the SEM images of treated cells showed wrinkled and damaged cell walls, indicating the disruption and disorganization of the membrane. This study showed that the synthesized NPs were effective in inhibiting the growth of drug-resistant bacteria, candida, and their preformed biofilms as well. Thus, these NPs with broad-spectrum applications could be exploited in medical settings to diminish biofilm-based infections caused by these pathogenic strains.

Background: The reporting of adverse drug reactions associated with drug-resistant tuberculosis (DR-TB) medication is important for pharmacovigilance, especially in high-burden countries such as South Africa. With DR-TB treatment being so dynamic, it is important to understand adverse event reporting practices at specialised facilities. Objectives: The study aimed to understand the adverse drug reaction (ADR) reporting practices at DR-TB treatment facilities in South Africa. Method: Interviews were conducted with healthcare workers at specialised DR-TB facilities. This was to collect data on demographics, pharmacovigilance training, and determine attitudes and practices towards reporting adverse events. A checklist was developed to review the most recent adverse event forms captured at the facility. Results: Most participants did not have adverse event reporting training since their initial training but were confident that they could complete a form themselves. Most participants could correctly identify the major adverse events associated with DR-TB medication, but some deemed non-adverse events as plausible. Adverse event report forms were not standardised with most participants deeming further training and regular feedback as reasons to report ADRs. Conclusion: Standardisation of adverse event report forms used and the establishment of regular reporting will increase adverse event reporting at DR-TB facilities. Continuous training, empowerment and expansion of staff categories eligible to report adverse events will enhance and sustain such practice. Contribution: The study highlights challenges faced by healthcare professionals in reporting adverse events.

Objective: The objective of this study is to determine the drug resistance status of pulmonary tuberculosis patients in Jilin Province. Methods: A retrospective survey was conducted on 395 sputum culture TBpositive patients admitted to the tuberculosis hospital in Jilin Province in 2019. Sputum samples were cultured in acidic Roche medium. Drug sensitivity testing was conducted using the proportional method. Sensitivity was reported if the percentage of drug resistance was less than 1%, and resistance was reported if the percentage was ≥1%. Statistical analysis was performed using SPSS 22.0. Results: 395 tuberculosis patients with positive sputum tuberculosis culture were included in the study, with 102 being initially treated and 293 being retreated. The study population consisted of 283 males and 112 females. Sex, age, nationality, occupation, marital status, diabetes comorbidity, initial treatment, normal health status, BCG vaccine vaccination, smoking, and alcohol consumption were considered as factors that may affect the rate of multidrug resistance. And only the history of treatment (initial treatment) was associated with multidrug resistance (p = 0.032). This indicates that retreatment is the most significant risk factor for the occurrence of multidrug resistance in tuberculosis. The multidrug resistance rate in retreated patients is 3.764 times higher than that in initially treated patients. Conclusion: The prevalence of multidrug-resistant is higher in retreated patients compared to initially treated patients in the study population. Multidrug resistance is only associated with the treatment history (initial retreatment) and not with other factors. [ABSTRACT FROM AUTHOR]

With only four classes of antifungal drugs available for the treatment of invasive systemic fungal infections, the number of resistant fungi is increasing, highlighting the urgent need for novel antifungal drugs. Ergosterol, an essential component of cell membranes, and its synthetic pathway have been targeted for antifungal drug development. Sterol-C4-methyl monooxygenase (Erg25p), which is a greater essential target than that of existing drugs, represents a promising drug target. However, the development of antifungal drugs must consider potential side effects, emphasizing the importance of evaluating their selective toxicity against fungi. In this study, we knocked in ERG25 of Candida glabrata and its human ortholog, SC4MOL, in ERG25-deleted Saccharomyces cerevisiae. Utilizing these strains, we evaluated 1181-0519, an Erg25p inhibitor, that exhibited selective toxicity against the C. glabrata ERG25 knock-in strain. Furthermore, 1181-0519 demonstrated broad-spectrum antifungal activity against pathogenic Candida species, including Candida auris. The approach of utilizing a gene that is functionally conserved between yeast and humans and subsequently screening for molecular target drugs enables the identification of selective inhibitors for both species. [ABSTRACT FROM AUTHOR]

Background: To overcome cisplatin resistance, the cytotoxicity of a novel antitumor agent on two ovarian cancer cell lines sensitive and resistant to cisplatin was investigated. Methods: MTT assay and flow cytometry were performed to assess the cytotoxicity of a novel water-soluble Pd (II) complex, [Pd(bpy)(pyr-dtc)]NO3 (PBPD), on cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. Furthermore, variations in the expression of drug resistance gene cluster of differentiation 99 (CD99), signal transducer and activator of transcription 3 (STAT3), octamer-binding transcription factor 4 (OCT4), and multidrug resistance mutation 1 (MDR1) were evaluated using Real-Time PCR. Results: The IC50 values of PBPD in resistant cells were higher than those in sensitive cells. Furthermore, PBPD has a deadlier effect on sensitive cells compared to resistant cells, and the cell survival rate is reduced over time. Flow cytometry revealed that PBPD enhanced the population of living-resistant cells while driving them to apoptosis. PBPD, on the other hand, has a greater effect on the living cell population and has dramatically shifted the population toward apoptosis and necrosis in the sensitive cells. Furthermore, gene expression analysis showed that when sensitive and resistant cells were treated with cisplatin, all resistance genes increased significantly relative to the control. In contrast to OCT4, MDR1, STAT3, and CD99 resistance genes were not significantly elevated in sensitive cells treated with PBPD compared to the control. Thus, the expression of resistance genes in resistant cells treated with PBPD was lower than cisplatin. Conclusions: As a result, PBPD is a promising anticancer agent for CDDP-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice. [ABSTRACT FROM AUTHOR]

Drug resistance substantially compromises antibiotic therapy and poses a serious threat to public health. Fusidic acid (FA) is commonly used to treat staphylococcal infections, such as pneumonia, osteomyelitis and skin infections. However, Gram-negative bacteria have natural resistance to FA, which is almost restrained in cell membranes due to the strong interactions between FA and phospholipids. Herein, we aim to utilize the strong FA–phospholipid interaction to pre-form a complex of FA with the exogenous phospholipid. The FA, in the form of an FA–phospholipid complex (FA-PC), no longer interacts with the endogenous membrane phospholipids and thus can be delivered into bacteria cells successfully. We found that the water solubility of FA (5 µg/mL) was improved to 133 µg/mL by forming the FA-PC (molar ratio 1:1). Furthermore, upon incubation for 6 h, the FA-PC (20 µg/mL) caused a 99.9% viability loss of E. coli and 99.1% loss of P. aeruginosa, while free FA did not work. The morphology of the elongated bacteria cells after treatment with the FA-PC was demonstrated by SEM. The successful intracellular delivery was shown by confocal laser scanning microscopy in the form of coumarin 6-PC (C6-PC), where C6 served as a fluorescent probe. Interestingly, the antibacterial effect of the FA-PC was significantly compromised by adding extra phospholipid in the medium, indicating that there may be a phospholipid-based transmembrane transport mechanism underlying the intracellular delivery of the FA-PC. This is the first report regarding FA-PC formation and its successful reversing of Gram-negative bacteria resistance to FA, and it provides a platform to reverse transmembrane delivery-related drug resistance. The ready availability of phospholipid and the simple preparation allow it to have great potential for clinical use.

ABSTRACT A novel oxazolidinone for the treatment of Mycobacterium tuberculosis has been developed, but the activity of contezolid (MRX-I) still needs to be clarified. In this study, we isolated Mycobacterium tuberculosis from 48 clinical patients with pulmonary tuberculosis. Roche drug susceptibility tests identified drug-sensitive and 39 drug-resistant M. tuberculosis isolates. Drug susceptibility assays indicated that MRX-I exhibited anti-Mycobacterium tuberculosis activity against both drug-sensitive and drug-resistant isolates, with an advantage against drug-resistant isolates. The results also showed that the anti-Mycobacterium tuberculosis activity was comparable to that of linezolid. IMPORTANCE Currently, Mycobacterium tuberculosis has exhibited increased drug resistance, leading to ineffective drug treatment in many patients with tuberculosis. Among the anti-Mycobacterium tuberculosis drugs, oxazolidinones have been gradually developed. Contezolid (MRX-I) has been newly developed in China with advantages versus the first oxazolidinone antibiotic approved by the Food and Drug Administration for clinical use, but the anti-M. tuberculosis activity needs to be further clarified. In this study, in vitro activities of MRX-I against M. tuberculosis were tested. The drug susceptibility assays indicated that MRX-I exhibited anti-M. tuberculosis activity comparable to that of linezolid, with an advantage against drug-resistant isolates.

ABSTRACT Clofazimine (CFZ) has been repurposed for treating tuberculosis (TB), especially multidrug-resistant tuberculosis (MDR-TB). However, the mechanisms of resistance to clofazimine are poorly understood. We previously reported a mutation located in the intergenic region of Rv1453 that was linked to resistance to CFZ and demonstrated that an Rv1453 knockout resulted in an increased minimum inhibitory concentration (MIC) of CFZ. The current study aims to go back and describe in detail how the mutation was identified and further explore its association with CFZ resistance by testing additional 30 isolates. We investigated MICs of clofazimine against 100 clinical strains isolated from MDR-TB patients by microplate alamarBlue assay. Whole-genome sequencing (WGS) was performed on 11 clofazimine-resistant and 7 clofazimine-susceptible strains, including H37Rv. Among the 11 clofazimine-resistant mutants subjected to WGS, the rate of mutation in the intergenic region of the Rv1453 gene was 55% (6/11) in clofazimine-resistant strains. Among another 30 clofazimine-resistant clinical isolates, 27 had mutations in the intergenic region of the Rv1453 gene. A mutation in the Rv1453 gene associated with clofazimine resistance was identified, which shed light on the mechanisms of action and resistance of clofazimine. IMPORTANCE Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis, especially the emergence of multidrug-resistant tuberculosis (MDR-TB) brings great distress to humans. Clofazimine (CFZ) plays an important role in the treatment of MDR-TB. To understand the underlying mechanism of clofazimine resistance better, in this study, we review and detail the findings of the mutation of intergenic region of Rv1453 and find additional evidence that this mutation is related to clofazimine resistance in 30 additional isolates. The significance of our research is to contribute to a comprehensive understanding of clofazimine-resistant mechanisms, which is critical for reducing the emergence of resistance and for anti-TB drug discovery.

Human epidermal growth factor receptor 2 (HER2) plays a critical role in breast cancer progression in patients with HER2 overexpression, thereby driving the development of targeted drugs and advancing therapy strategies targeting this gene. Pyrotinib is a novel irreversible pan-ErbB kinase inhibitor, primarily suppresses the downstream MAPK and PI3K/AKT pathways. Alpelisib, a selective PI3K p110α inhibitor, has been approved for clinical application in HR+, HER2-, PIK3CA mutated breast cancers and is also being developed for use in other breast cancer subtypes. In this study, we hypothesised that combining pyrotinib with alpelisib would yield superior results compared to single-drug treatment. Our data demonstrated that the combination of alpelisib and pyrotinib exhibited a synergistic effect in HER2+ breast cancer both in vitro and in vivo. This combination led to decreased cell proliferation and migration, G0-G1 cell cycle arrest, and increased apoptosis rates. Additionally, the deactivation of ErbB receptors and sustained activation of PI3K/AKT pathway by upstream compensatory pathways induced acquired pyrotinib resistant cells resistant to pyrotinib treatment, thus alpelisib combined with pyrotinib showed a tremendous synergistic effect and reverse pyrotinib resistance in acquired pyrotinib resistant cells by suppressing the activated PI3K/AKT pathway. Our results revealed a combination of pyrotinib and alpelisib as an effective therapeutic strategy in treating HER2+ breast cancer, whether sensitive or resistant to pyrotinib treatment.

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian carcinoma that responds poorly to chemotherapy. Glutathione (GSH) is a primary antioxidant, which protects cells against reactive oxygen species (ROS). High levels of GSH are related to chemotherapeutic resistance. The glutamine/cystine transporter xCT is essential for intracellular GSH synthesis. However, whether xCT inhibition can overcome the resistance to chemotherapeutic agents in OCCC remains unclear. This study demonstrated that combined treatment with paclitaxel (PTX) and the xCT inhibitor sulfasalazine (SAS) significantly enhanced cytotoxicity more than the individual drugs did in OCCC cells. Treatment with PTX and SAS induced apoptosis more effectively than did individual drug treatments in the cells with significant generation of ROS. Moreover, combined treatment with PTX and SAS induced ferroptosis in the cells with low expression of glutathione peroxidase (GPx4), high levels of intracellular iron and significant lipid ROS accumulation. Therefore, our findings provide valuable information that the xCT inhibitor might be a promising therapeutic target for drug-resistant OCCC. The strategy of combined administration of PTX and SAS can potentially be used to treat OCCC and help to develop novel therapeutic methods. [ABSTRACT FROM AUTHOR]

Objective: The pathophysiology of epilepsy remains unknown. Recent research has shown that microRNA expression changes in epileptic adults. In the present work, we aimed to identify serum microRNA expression in drug-responsive and resistant children with idiopathic generalized epilepsy. Materials and Methods: The study included 43 (20 male and 23 female) epilepsy patients and 66 (43 male and 23 female) control subjects. The mean ages of the groups were 113.41 ± 61.83 and 105.46 ± 62.31 months, respectively. Twenty-eight epileptic patients were classified as drug resistant. Thirteen of the controls were the siblings of patients with epilepsy. The study only included children with idiopathic generalized epilepsy who had normal brain magnetic resonance imaging. The serum microRNA expressions (microRNA-181a, microRNA-155, microRNA-146, and microRNA-223) were investigated. Expressions of serum microRNA-181a, microRNA-155, microRNA-146, and microRNA-223 were previously investigated in epilepsy patients and children with febrile seizures. Therefore, these microRNAs were chosen. The expressions of serum levels of microRNAs were determined using quantitative real-time polymerase chain reaction. Results: The results indicated that the expressions of serum microRNA-155 and microRNA-223 were elevated in epileptic children (P < .05). The expression of the same microRNAs was also elevated in individuals with drug-resistant epilepsy compared to healthy controls (P < .05). microRNA-146a, microRNA-155, and microRNA-223 expressions were higher in drug-resistant patients than in drug-responsive children (P < .05). A logistic regression study determined that an increase of microRNA-155 was a risk for epilepsy, while a decrease of microRNA-146a risk for epilepsy. Conclusion: Few researchers have investigated the function of microRNAs in the development of childhood epilepsy. Our findings revealed that epilepsy patients have abnormal microRNAexpression. [ABSTRACT FROM AUTHOR]

Background: There is no published case of diastolic dysfunction arising due to bedaquiline treatment for Multi-Drug Resistant Tuberculosis (MDR-TB). Diastolic dysfunction is not listed as a potential complication of treatment with bedaquiline. This case report is the first to link bedaquiline to diastolic dysfunction. Clinicians should be aware of this potential complication, and ensure that patients are monitored and investigated appropriately. Case Presentation: A 47 year old female presented with fever, productive cough and drenching night sweats for more than 2 weeks prior to presentation. There was no hemoptysis, chest pains or weight loss. She however, felt breathless after a heavy bout of coughing. Fever was intermittent, and most pronounced at night. The patient denied any weight loss over the past month. The patient had no history of HIV, diabetes, hypertension or heart disease. There were no previous episodes of TB. There was history of contact with a patient with MDR-TB patient. The patients' son, who shared a house and all living spaces with the patient, was being treated for MDR-TB at the time of presentation. The patient did not drink or smoke. There was no history of illicit drug use. She worked as a restaurant manager. Due to the history of very close contact with MDR-TB, the patient was commenced on the longer, oral only regimen for MDR-TB which includes bedaquiline. Four weeks after commencement of bedaquiline, the patient complained that both feet were swelling. There were no other symptoms or signs of cardiovascular disease. An Echocardiogram done during the fifth month showed an ejection fraction of 71% and diastolic dysfunction. The patient was commenced on diuretics and continued on MDRTB treatment. An echocardiogram that was repeated at month 15 review showed an ejection fraction of 64%, normal left ventricle and normal systolic and diastolic function. Conclusions: Diastolic Dysfunction has not previously been reported in patients on bedaquiline. This is the first case report to link bedaquiline to diastolic dysfunction. More studies need to be done to determine conclusively whether bedaquiline can cause diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one‐third of epilepsy patients experience seizures despite therapy. Drug‐resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3–13.4 times higher mortality rate than in seizure‐free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic–clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long‐term, open‐label studies, 10%–36% of patients were seizure‐free for a median duration of ~30–45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open‐label extension studies. Mortality was reduced 5‐fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post‐launch information about the efficacy and safety of these ASMs. [ABSTRACT FROM AUTHOR]

Background: Infections caused by Myroides spp. have been found very rarely in recent scientific literature. These Gram-negative bacilli however are increasingly being implicated in various life threatening infections, of late, in some of the critical care settings. Objective: To detect Myroides spp infections with strong degree of suspicion and to review the surveillance of multi drug resistant organism spread and containment in critical care settings of hospital. Methodology: Suspected isolates were found in the course of routine laboratory activities of blood and urine culture from patients admitted in intensive care unit, from amongst the non -fermenter Gram negative bacteria set as the inclusion criterion, and subjected to identification and antimicrobial susceptibly testing in automated system following standard microbiological methodology by Vitek-2 automated identification and susceptibility testing system. Interpretation of the results was done following the guidelines of Clinical and laboratory standards Institute. History and other relevant investigation results, as required, of the patients were retrieved from hospital record section. Result: Out of the 620 non-fermenter gram negative bacilli included in the study, Myroides spp. isolates were found five in number from blood and urine samples of the five patients. Tigecycline and minocycline were found to be most effective drug against the organism followed by colistin and imipenem. Conclusion: A robust Antimicrobial stewardship policy and implementation tool with efficient infection control measures are backbone to limit emergence and spread of such microbes in unforeseen days.

Shufang Lin,1 Shuzhen Wei,1 Yong Zhao,1 Zhisong Dai,1 Jian Lin,1 Yu Pang2 1Fujian Provincial Key Laboratory of Zoonosis Research, Fujian Center for Disease Control and Prevention, Fuzhou, People’s Republic of China; 2Department of Bacteriology and Immunology, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of ChinaCorrespondence: Shuzhen Wei, Fujian Center for Disease Control and Prevention, No. 386, Chong’an Road, Jin’an District, Fuzhou, Fujian, 350012, People’s Republic of China, Tel/Fax +86 591 8343 1464, Email 499277975@qq.com Yu Pang, Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86 10 8950 9359, Email pangyupound@163.comBackground: Here, we aimed to determine the population structure of Mycobacterium tuberculosis (MTB) genotypes in Fujian and explore risk factors associated with infection with the Beijing genotype. We also explored the association between Beijing genotype and drug resistance.Methods: Representative MTB isolates obtained during provincial-level routine anti-tuberculosis drug resistance surveillance conducted since 2013 in 11 Fujian counties were analyzed using McSpoligotyping. In vitro drug susceptibilities to anti-tuberculosis drugs were determined using the standard Löwenstein–Jensen proportion method.Results: Overall, 477 MTB isolates were included in the study, of which 245 isolates belonged to the Beijing genotype family and 232 possessed non-Beijing genotypes. Ultimately, a total of 204 spoligotypes were identified that included 58 spoligotype international types (SITs) from the SITVITWEB database and 146 novel spoligotypes. As compared to patients < 25 years of age (control group), elderly patients (≥ 65 years of age) were more likely to be infected with non-Beijing genotypes [aOR 18.69, 95% CI (5.80– 60.26)], with risk of infection with non-Beijing genotypes increasing with age [aOR 3.73, 95% CI (1.67– 8.30) for patients 45– 64 years of age]. Additionally, as compared to isolates with Beijing and other non-Beijing genotypes, significantly greater proportions of isolates with novel spoligotypes exhibited PTO- and PAS-resistance. Moreover, a markedly higher proportion of isolates with novel spoligotypes exhibited OFX-resistance as compared to isolates with other non-Beijing genotypes.Conclusion: Our data demonstrated that the Beijing genotype is the predominant MTB sublineage in Fujian and that the prevalence rate of infection with this MTB genotype decreases with advancing patient age. Notably, the prevalence rate of this genotype in Fujian TB patients is relatively lower than in other regions of China. In addition, the emergence of novel spoligotypes of highly drug-resistant MTB isolates highlights the urgent need for ongoing molecular genotyping surveillance in Fujian.Keywords: Mycobacterium tuberculosis, genotype, spoligotype, drug resistant

Mycobacterium tuberculosis (MTB) causes one of the ancient diseases, Tuberculosis, affects people around the globe and its severity can be understood by its classification as a second infectious disease after COVID-19 and the 13th leading cause of death according to a WHO report. Despite having advanced diagnostic approaches and therapeutic strategies, unfortunately, TB is still spreading across the population due to the emergence of drug-resistance MTB and Latent TB infection (LTBI). We are seeking for effective approaches to overcome these hindrances and efficient treatment for this perilous disease. Therefore, there is an urgent need to develop drugs based on operative targeting of the bacterial system that could result in both efficient treatment and lesser emergence of MDR-TB. One such promising target could be the secretory systems and especially the Type 7 secretory system (T7SS-ESX) of Mycobacterium tuberculosis, which is crucial for the secretion of effector proteins as well as in establishing host–pathogen interactions of the tubercle bacilli. The five paralogous ESX systems (ESX-1 to EXS-5) have been observed by in silico genome analysis of MTB, among which ESX-1 and ESX-5 are substantial for virulence and mediating host cellular inflammasome. The bacterium growth and virulence can be modulated by targeting the T7SS. In the present review, we demonstrate the current status of therapeutics against MTB and focus on the function and cruciality of T7SS along with other secretory systems as a promising therapeutic target against Tuberculosis. [ABSTRACT FROM AUTHOR]

The prevalence of antibiotic-resistant diseases drives a constant hunt for new substitutes. Metal-containing inorganic nanoparticles have broad-spectrum antimicrobial potential to kill Gram-negative and Gram-positive bacteria. In this investigation, reduced graphene oxide-coated zinc oxide–copper (rGO@ZnO–Cu) nanocomposite was prepared by anchoring Cu over ZnO nanorods followed by coating with graphene oxide (GO) and subsequent reduction of GO to rGO. The synthesized nanocomposite was characterized by scanning electron microscopy, transmission electron microscopy, elemental analysis, and elemental mapping. Morphologically, ZnO–Cu showed big, irregular rods, rectangular and spherical-shaped ZnO, and anchored clusters of aggregated Cu particles. The Cu aggregates are spread uniformly throughout the network. Most of the ZnO particles were partially covered with Cu aggregates, while some of the ZnO was fully covered with Cu. In the case of rGO@ZnO–Cu, a few layered rGO sheets were observed on the surface as well as deeply embedded inside the network of ZnO–Cu. The rGO@ZnO–Cu complex exhibited antimicrobial activity against Gram-positive and Gram-negative bacteria; however, it was more effective on Staphylococcus aureus than Escherichia coli. Thus, rGO@ZnO–Cu nanocomposites could be an effective alternative against Gram-positive and Gram-negative bacterial pathogens. [ABSTRACT FROM AUTHOR]

IntroductionThis study aims to develop a web application, TB-DRD-CXR, for the categorization of tuberculosis (TB) patients into subgroups based on their level of drug resistance. The application utilizes an ensemble deep learning model that classifies TB strains into five subtypes: drug sensitive tuberculosis (DS-TB), drug resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), pre-extensively drug-resistant TB (pre-XDR-TB), and extensively drug-resistant TB (XDR-TB).MethodsThe ensemble deep learning model employed in the TB-DRD-CXR web application incorporates novel fusion techniques, image segmentation, data augmentation, and various learning rate strategies. The performance of the proposed model is compared with state-of-the-art techniques and standard homogeneous CNN architectures documented in the literature.ResultsComputational results indicate that the suggested method outperforms existing methods reported in the literature, providing a 4.0%-33.9% increase in accuracy. Moreover, the proposed model demonstrates superior performance compared to standard CNN models, including DenseNet201, NASNetMobile, EfficientNetB7, EfficientNetV2B3, EfficientNetV2M, and ConvNeXtSmall, with accuracy improvements of 28.8%, 93.4%, 2.99%, 48.0%, 4.4%, and 7.6% respectively.ConclusionThe TB-DRD-CXR web application was developed and tested with 33 medical staff. The computational results showed a high accuracy rate of 96.7%, time-based efficiency (ET) of 4.16 goals/minutes, and an overall relative efficiency (ORE) of 100%. The system usability scale (SUS) score of the proposed application is 96.7%, indicating user satisfaction and a likelihood of recommending the TB-DRD-CXR application to others based on previous literature.

ABSTRACT: Pasteurella multocida (P. multocida) is a zoonotic bacterium that can cause diseases in a variety of animals. It was divided into 5 serogroups, and serogroup A is mainly prevalent in avian hosts. We isolated a virulent and multidrug-resistant P. multocida strain from Guangdong duck liver and named it PMWSG-4 (GenBank accession no. CP077723.1). To understand the pathogenicity of this strain, the pathogenicity test was carried out with mice and ducks. The results showed that PMSWG-4 was highly pathogenic to ducks and mice, and the LD50 is 4.5 and 73 CFU, respectively. In order to study its genetic characteristics, pathogenicity, and relationship with the host, we performed a whole genome sequencing. The genome size of the isolated PMWSG-4 was 2.38 Mbp, with a G+C content of 40.3%, and coding 2,313 Coding DNA Sequence (CDS). The genome carries 162 potential virulence-associated genes, 32 different drug resistance phenotypes, 102 genes possibly involved in pathogen–host interaction, 2 gene island groups, and 4 prophages. In addition, we also found a new drug-resistant plasmid from strain PMWSG-4, named pXL001 (GenBank accession no. CP077724.1). After verified, the plasmid is a new plasmid carrying the floR florfenicol resistance gene. The whole genome is of great significance for further studying the pathogenesis and genetic characteristics of duck-derived P. multocida.

Background: The reporting of adverse drug reactions associated with drug-resistant tuberculosis (DR-TB) medication is important for pharmacovigilance, especially in high-burden countries such as South Africa. With DR-TB treatment being so dynamic, it is important to understand adverse event reporting practices at specialised facilities. Objectives: The study aimed to understand the adverse drug reaction (ADR) reporting practices at DR-TB treatment facilities in South Africa. Method: Interviews were conducted with healthcare workers at specialised DR-TB facilities. This was to collect data on demographics, pharmacovigilance training, and determine attitudes and practices towards reporting adverse events. A checklist was developed to review the most recent adverse event forms captured at the facility. Results: Most participants did not have adverse event reporting training since their initial training but were confident that they could complete a form themselves. Most participants could correctly identify the major adverse events associated with DR-TB medication, but some deemed non-adverse events as plausible. Adverse event report forms were not standardised with most participants deeming further training and regular feedback as reasons to report ADRs. Conclusion: Standardisation of adverse event report forms used and the establishment of regular reporting will increase adverse event reporting at DR-TB facilities. Continuous training, empowerment and expansion of staff categories eligible to report adverse events will enhance and sustain such practice. Contribution: The study highlights challenges faced by healthcare professionals in reporting adverse events. [ABSTRACT FROM AUTHOR]

• Differentiation of Drug Sensitive and Resistant Tuberculosis using chest X-rays. • Both lungs and mediastinum are precisely segmented using active contour models. • Significant lung and mediastinum shape features are extracted for characterization. • Multilayer perceptron and support vector machine classifiers perform better. • Combination of mediastinum and lung features improves the diagnostic accuracy. The rise of Drug Resistant Tuberculosis (DR TB), particularly Multi DR (MDR), and Extensively DR (XDR) has reduced the rate of control of the disease. Computer aided diagnosis using Chest X-rays (CXRs) can help in mass screening and timely diagnosis of DR TB, which is essential to administer proper treatment regimens. In CXRs, lungs and mediastinum are two significant regions which contain the information about the likelihood of DR TB. The objective of this work is to analyze the shape characteristics of lungs and mediastinum to improve the diagnostics accuracy for differentiation of Drug Sensitive (DS), MDR and XDR TB using computer aided diagnostics system. The CXR images of DS and DR TB patients are obtained from a public database. The lung fields are segmented from the CXRs using Reaction Diffusion Level Set Evolution. Mediastinum is segmented from the delineated lung masks using Chan Vese model. The shape features from each lung and mediastinum masks are extracted and analysed. The discriminative power of individual and combination of both lung and mediastinum features are evaluated using machine learning techniques for classification of DS vs MDR, MDR vs XDR and DS vs XDR TB images. The performances of classifiers are compared using standard metrics. The proposed segmentation methods are able to delineate lungs and mediastinum from the CXR images. The extracted lung and mediastinum features are found to be statistically significant (p < 0.05) for differentiation of DS and DR TB conditions. Using the combination of both lung and mediastinum features, Multi-Layer Perceptron classifier achieves maximum F-measure of 82.4%, 81.0% and 87.0% for differentiation of DS vs MDR, MDR vs XDR and DS vs XDR, respectively. Analysis of mediastinum along with the lungs in chest X-rays could improve the diagnostic performance for differentiation of drug sensitive and resistant TB conditions. The proposed methodology is able to differentiate DS, MDR and XDR TB, and found to be clinically relevant. Hence, this work is useful for computer-based early detection of DS and DR TB conditions. [ABSTRACT FROM AUTHOR]

Excessive antibiotic prescriptions as well as their misuse in agriculture are the main causes of antimicrobial resistance which poses a growing threat to public health. It necessitates the search for novel chemicals to combat drug resistance. Since ancient times, naturally occurring medicines have been employed and the enormous variety of bioactive chemicals found in nature has long served as an inspiration for researchers looking for possible therapeutics. Secondary metabolites from microorganisms, particularly those from actinomycetes, have made it incredibly easy to find new molecules. Different actinomycetes species account for more than 70% of naturally generated antibiotics currently used in medicine, and they also produce a variety of secondary metabolites, including pigments, enzymes, and anti-inflammatory compounds. They continue to be a crucial source of fresh chemical diversity and a crucial component of drug discovery. This review summarizes some uncommon sources of antifungal metabolites and highlights the importance of further research on these unusual habitats as a source of novel antimicrobial molecules. [ABSTRACT FROM AUTHOR]

Drug-resistant pathogens are seriously threatening global public health. It is urgent to discover new drugs that can effectively inhibit drug-resistant bacteria. Carbon quantum dots (CQDs), as a good antibacterial agent, have gained considerable interest due to their green synthesis method and low toxicity. In this work, the Si-doped CQDs with bright blue fluorescence are prepared by one-step hydrothermal method using glycyrrhizic acid and methyltrimethoxysilane. The average particle diameter of Si-doped CQD with emission at 420 nm is found to be 2.10 nm. The Si-doped CQDs exhibit a good antibacterial activity against Escherichia coli and Staphylococcus aureus with MIC of 1.25 mg/mL, but it does not show selectivity. Furthermore, the antibacterial mechanism of Si-doped CQDs suggest that Si-doped CQDs destroy the normal morphology of bacteria by generating 1O2 and enter the interior of bacteria to produce antibacterial effects. The present study provides a strategy for the preparation of CQDs from a medicinal plant with antibacterial activities against two common pathogens. [ABSTRACT FROM AUTHOR]

Amina Nazir,1– 3 Chunling Qi,4 Na Shi,4 Xue Gao,4 Qiang Feng,4 Hong Qing,2 Fei Li,3,4 Yigang Tong3 1Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong Province, People’s Republic of China; 2Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Sciences, Beijing Institute of Technology, Beijing, People’s Republic of China; 3College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, People’s Republic of China; 4Clinical Laboratory Center, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, People’s Republic of ChinaCorrespondence: Fei Li; Yigang Tong, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, People’s Republic of China, Email lf-314@163.com; tong.yigang@gmail.comIntroduction: Klebsiella pneumoniae, a multidrug resistant bacterium, that causes nosocomial infections including septicemia, pneumonia etc. Bacteriophages are potential antimicrobial agents for the treatment of antibiotic resistant bacteria.Methods and Results: In this study, a novel bacteriophage IME268 was isolated from hospital sewage against clinical multi-drug resistant Klebsiella pneumoniae. Transmission electron microscopy and genomic characterization of this phage exhibited it belongs to the Webervirus genus, Drexlerviridae family. Phage IME268 possessed a double-stranded DNA genome composed of 49,552bp with a GC content of 50.5%. The phage genome encodes 77 open reading frames, out of 44 are hypothetical proteins while 33 had assigned putative functions. No tRNA, virulence related or antibiotic resistance genes were found in phage genome. Comparative genomic analysis showed that phage IME268 has 95% identity with 87% query cover with other phages in NCBI database. Multiplicity of infection, one step growth curve and host range of phage were also measured.Conclusion: According to findings, Phage IME268 is a promising biological agent that infects Klebsiella pneumoniae and can be used in future phage therapies.Keywords: Klebsiella pneumoniae, bacteriophage, therapy, lytic, drug resistant

With only four classes of antifungal drugs available for the treatment of invasive systemic fungal infections, the number of resistant fungi is increasing, highlighting the urgent need for novel antifungal drugs. Ergosterol, an essential component of cell membranes, and its synthetic pathway have been targeted for antifungal drug development. Sterol-C4-methyl monooxygenase (Erg25p), which is a greater essential target than that of existing drugs, represents a promising drug target. However, the development of antifungal drugs must consider potential side effects, emphasizing the importance of evaluating their selective toxicity against fungi. In this study, we knocked in ERG25 of Candida glabrata and its human ortholog, SC4MOL, in ERG25-deleted Saccharomyces cerevisiae. Utilizing these strains, we evaluated 1181-0519, an Erg25p inhibitor, that exhibited selective toxicity against the C. glabrata ERG25 knock-in strain. Furthermore, 1181-0519 demonstrated broad-spectrum antifungal activity against pathogenic Candida species, including Candida auris. The approach of utilizing a gene that is functionally conserved between yeast and humans and subsequently screening for molecular target drugs enables the identification of selective inhibitors for both species.

We report the case of a 46-year-old patient who, after renal cancer surgery, developed a recurrent urinary tract infection that lasted for more than 2 years. Despite repeated antibiotic courses, including broad-spectrum drugs chosen using conventional antibiotic susceptibility testing, multiple reinfections followed. The patient was successfully treated once antibiotics were selected with AtbFinder. Unlike routine antimicrobial susceptibility methods, which select antibiotics effective only against a “lead bacterial pathogen,” AtbFinder identifies antibiotics that target the mixture of bacteria at the infection site. This case demonstrates the ability of AtbFinder to successfully select antibiotics for the treatment of relapsing urinary tract infections.

Human malaria continues to be a public health problem and an important cause of morbidity and mortality in the world. Malaria control is achieved through both individual protection against mosquito bites and drug treatment, which is hampered by the spread of Plasmodium falciparum resistance to most antimalarials, including artemisinin derivatives. One of the key pharmacological strategies for controlling malaria is to block transmission of the parasites to their mosquito vectors. Following this rational, MEFAS, a synthetic hybrid salt derived from artesunate (AS) and mefloquine has been previously reported for its activity against asexual P. falciparum parasites in vitro, in addition to a pronounced reduction in the viability of mature gametocytes. Herein, MEFAS was tested against asexual forms of Plasmodium vivax and for its ability to block malaria transmission in Anopheles darlingi mosquitoes in a membrane feeding assay using P. vivax field isolates. MEFAS demonstrated high potency, with a IC50 of 6.5 nM against asexual forms of P. vivax. At 50 μM, MEFAS completely blocked oocyst formation in mosquitoes, regardless of the oocyst number in the control group. At lower doses, MEFAS reduced oocyst prevalence by greater than 20%. At equivalent doses, AS irregularly reduced oocyst formation and caused only slight inhibition of mosquito infections. These results highlight the potential of MEFAS as a novel transmission-blocking molecule, as well as its high blood schizonticidal activity against P. vivax and P. falciparum field isolates, representing a starting point for further development of a new drug with dual antimalarial activity.