Multidrug-resistant tuberculosis clusters and transmission in Taiwan: a population-based cohort study.

Introduction: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge in the TB program of Taiwan, where 0.5% of new cases and 2.1% of previously treated cases were resistant to at least rifampin (RIF) and isoniazid (INH). Since >80% of our MDR-TB are new cases, genotyping of MDR Mycobacterium tuberculosis is implemented to facilitate contact investigation, cluster identification, and outbreak delineation. Methods: This is a population-based retrospective cohort study analyzing MDR-TB cases from 2019 to 2022. Whole genome sequencing (WGS) was performed using the Illumina MiSeq and analyzed using the TB Profiler. A single nucleotide polymorphism (SNP) threshold of ≤ 12 and phylogenetic methods were used to identify putative transmission clusters. An outbreak was confirmed using genomic data and epidemiologic links. Results: Of the 297 MDR-TB cases, 246 (82.8%), 45 (15.2%), and 6 (2.0%) were simple MDR, extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), respectively. The sublineage 2.2 modern Beijing was the predominant (48.8%) MDR-TB strain in Taiwan. Phylogenetic analysis identified 25.3% isolates in 20 clusters, with cluster sizes ranging from 2 to 13 isolates. Nevertheless, only 2 clusters, one household and one community, were confirmed as outbreaks. In this study, we found that males had a higher risk of MDR-TB transmission compared to females, and those infected with the sublineage 2.1-proto-Beijing genotype isolates were at a higher risk of transmission. Furthermore, 161 (54.2%) isolates harbored compensatory mutations in the rpoC and non-rifampicin resistant determinant region (non-RRDR) of the rpoB gene. MDR-TB strains containing rpoB S450L and other compensatory mutations concurrently were significantly associated with clusters, especially the proto-Beijing genotype strains with the compensatory mutation rpoC E750D or the modern Beijing genotype strains with rpoC D485Y/rpoC E1140D. Discussion: Routine and continuous surveillance using WGS-based analysis is recommended to warn of risks and delineate transmission clusters of MDR-TB. We proposed the use of compensatory mutations as epidemiological markers of M. tuberculosis to interrupt putative MDR-TB transmission.

Occurrence of Extended-spectrum ß-lactamase (ESBL) and Carbapenemase-producing Escherichia coli isolated from Childhood Diarrhoea in Yaoundé, Cameroon.

INTRODUCTION: Extended-spectrum ß-lactamase (ESBL)-producing pathogenic E. coli is a global public health issue, especially in sub-Saharan African countries such as Cameroon. It contributes to increase significantly hospital length of stay, morbidity, mortality and economic costs because of treatment failures. This study aims at determining the resistance background and virulence profiles of ESBL-E. coli isolates among childhood diarrhoea during the cholera outbreak occuring in Yaoundé, Cameroon. MATERIALS AND METHODS: During a four-month periods, from March 1st to June 30th, 2023,  a total of 84 stool samples were collected from 90 under five children presenting clinical signs of gastroenteritis and attending four hospitals in Yaoundé, Cameroon. Bacterial identification was done using API20E and antimicrobial susceptibility test was performed using the Kirby-Bauer disc diffusion method. After extraction, genomic DNA was subjected to conventional and multiplex polymerase chain reaction methods (PCRs) for detection of resistance and virulence genes. Statistical analysis was performed using Epi info™ (7.2.5.0). Statistical significance was considered at a p-value < 0.05. RESULTS: Out of 150 patients contacted, 90 patients were enrolled, 84 samples were collected, 52.38%(44/84) and 3.57%(03/84) were confirmed as extended-spectrum ß-lactamase and carbapenemase-producing E. coli respectively. The risk factors were analyzed, and children who drank natural fruit juice (OR: 0.4, p-value: 0.03) were found to be significantly associated with ESBL-producing E. coli. The ESBL-producing E. coli isolates showed a high level of resistance to amoxicillin-clavulanic acid, cefotaxime, ceftazidime, cefepime, colistin, and tetracycline. The blaCTX-M was more prevalent ß-lactamase resistance gene. The tetracycline resistance genes tet(A) and tet(B) were also detected. The most important virulence genes detected were FimH (81.81%) and papA (79.54%). CONCLUSION: These findings suggest implementing routine surveillance and screening for antimicrobial resistance among children under five. Antimicrobial stewardship strategies (ASP) need to be implemented to curb the emergence and dissemination of ESBL-producing E. coli. In addition, a national surveillance program for antimicrobial resistance needs to be implemented at local and regional levels in order to reduce morbidity in Cameroon.

Mutations across Diverse Domains of CjXDR1 Lead to Multidrug Resistance in Clarireedia jacksonii.

Recently, Clarireedia jacksonii has emerged as a significant pathogen threatening turfgrass, and its escalating resistance to multiple drugs often undermines field interventions. This study highlighted the critical role of the fungus-specific transcription factor CjXDR1 (formerly ShXDR1) in regulating multidrug resistance (MDR) in C. jacksonii. This was demonstrated through experiments involving CjXDR1-knockout and CjXDR1-complemented strains. Our sequence analysis revealed five mutations in CjXDR1: G445D, K453E, S607F, D676H, and V690A. All five gain-of-function (GOF) mutations were confirmed to directly contribute to MDR against three different classes of fungicides (propiconazole: demethylation inhibitor, boscalid: succinate dehydrogenase inhibitor, and iprodione: dicarboximide) using the genetic transformation system and in vitro fungicide-sensitivity assay. Comparative transcriptome analysis revealed that CjXDR1 and its GOF mutations led to the overexpression of downstream genes encoding a Phase I metabolizing enzyme (CYP68) and two Phase III transporters (CjPDR1 and CjAtrD) previously reported. Knockout mutants of CYP68, CjPDR1, CjAtrD, and double-knockout mutants of CjPDR1 and CjAtrD exhibited increased sensitivity to all three fungicides tested. Among these, the CYP68-knockout mutants displayed the highest sensitivity to propiconazole, while the CjPDR1 knockout mutant exhibited significantly increased sensitivity to all three fungicides. Double-knockout mutants of CjPDR1 and CjAtrD displayed greater sensitivity than the single knockouts. In conclusion, multiple GOF mutants in CjXDR1 contribute to MDR by upregulating the expression of CjPDR1, CjAtrD, and CYP68. This study enhances our understanding of the molecular mechanisms underlying MDR in plant pathogenic fungi, providing valuable insights into GOF mutation structures and advancing the development of antifungal drugs.

The gut microbiota of wild birds undergoing rehabilitation as a reservoir of multidrug-resistant enterococci in a metropolitan area in Brazil.

Enterococci are ubiquitous usually commensal bacteria that can act as opportunistic pathogens frequently associated with resistance to multiple antimicrobial classes. A variety of animals may carry potentially harmful enterococci. In the present work, the occurrence and characteristics of enterococci recovered from the fecal microbiota of wild birds belonging to four families (Accipitridae, Cathartidae, Falconidae and Strigidae) were investigated. Enterococci were recovered from 104 (92.0%) fecal samples obtained from 113 birds, and 260 strains were selected for additional characterization. Enterococcus faecalis was the predominant species (63.8%), followed by Enterococcus hirae (16.2%), Enterococcus faecium (11.5%), Enterococcus gallinarum (5.4%), Enterococcus avium (1.5%), Enterococcus casseliflavus (0.8%), and Enterococcus raffinosus and Enterococcus cecorum (0.4% each). Major percentages (11.9% 75.0%) of nonsusceptibility were observed to quinolones (particularly to enrofloxacin), erythromycin, rifampin, nitrofurantoin, tetracycline and streptomycin. Gentamicin and ampicillin resistances (13.3% each) were only detected among E. faecium. A total of 133 (51.2%) strains were MDR, showing a large variety of MDR profiles, composed by simultaneous resistance encompassing 3 to 12 antimicrobials. MDR strains were found in 68.2% of the birds. Antimicrobial resistance was associated with the presence of the aac(6')-aph(2″)-Ia, aph(2″)-Id, ant(6)-Ia, ant(9)-Ia, ant(9)-Ib, tet(M), tet(L), tet(S), erm(B), mef(A/E), msrC, and vat(D) genes. The most common virulence genes were efaA, gelE, ace, eeP, and asa1. PFGE analysis revealed a large genetic diversity among most of the strains. MLST performed for 35 E. faecalis strains revealed 23 different STs, whereas 14 STs were found among 18 E. faecium strains. Hospital-associated lineages ST22, ST25, ST56, ST1274 were identified. The results show that the wild birds investigated can carry a diversity of potentially hazardous enterococcal strains displaying multiple antimicrobial resistance and virulence genes, reinforcing the assumption that these animals provide an important target to monitor the circulation of microorganisms that deserve consideration under the One Health perspective.

Multidrug Resistance Reversed by Maleimide Interactions. A Biological and Synthetic Overview for an Emerging Field.

Multidrug Resistance (MDR) can be considered one of the most frightening adaptation types in bacteria, fungi, protozoa, and eukaryotic cells. It allows the organisms to survive the attack of many drugs used in the daily basis. This force the development of new and more complex, highly specific drugs to fight diseases. Given the high usage of medicaments, poor variation in active chemical cores, and self-medication, the appearance of MDR is more frequent each time, and has been established as a serious medical and social problem. Over the years it has been possible the identification of several genes and proteins responsible for MDR and with that the development of blockers of them to reach MDR reversion and try to avoid a global problem. These mechanisms also have been observed in cancer cells, and several calcium channel blockers have been successful in MDR reversion, and the maleimide can be found included in them. In this review we explore the history, mechanisms, reversion efforts, and we specifically focused on the maleimide synthesis as MDR-reversers in co-administration, as well as their biological applications in a urge to expand the available information and explore a very plausible MDR reversion source.

Endogenous Magnetic Lipid Droplet-Mediated Cascade-Targeted Sonodynamic Therapy as an Approach to Reversing Breast Cancer Multidrug Resistance.

Multidrug resistance (MDR) has emerged as a major barrier to effective breast cancer treatment, contributing to high rates of chemotherapy failure and disease recurrence. There is thus a pressing need to overcome MDR and to facilitate the efficient and precise treatment of breast cancer in a targeted manner. In this study, endogenous functional lipid droplets (IR780@LDs-Fe3O4/OA) were developed and used to effectively overcome the limited diffusion distance of reactive oxygen species owing to their amenability to cascade-targeted delivery, thereby facilitating precise and effective sonodynamic therapy (SDT) for MDR breast cancer. Initially, IR780@LDs-Fe3O4/OA was efficiently enriched within tumor sites in a static magnetic field, achieving the visualization of tumor treatment. Subsequently, the cascade-targeted SDT combined with the Fenton effect induced lysosome membrane permeabilization and relieved lysosomal sequestration, thus elevating drug concentration at the target site. This treatment approach also suppressed ATP production, thereby inhibiting P-glycoprotein-mediated chemotherapeutic drug efflux. This cascade-targeted SDT strategy significantly increased the sensitivity of MDR cells to doxorubicin, increasing the IC50 value of doxorubicin by approximately 10-fold. Moreover, the cascade-targeted SDT also altered the gene expression profiles of MDR cells and suppressed the expression of MDR-related genes. In light of these promising results, the combination of cascade-targeted SDT and conventional chemotherapy holds great clinical promise as an effective treatment modality with excellent biocompatibility that can improve MDR breast cancer patient outcomes.

High frequency of acquired virulence factors in carbapenemase-producing Klebsiella pneumoniae isolates from a large German university hospital, 2013-2021.

Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) isolates are a public health concern as they can cause severe hospital-acquired infections that are difficult to treat. It has recently been shown that CP-Kp can take up virulence factors from hypervirulent K. pneumoniae lineages. In this study, 109 clinical CP-Kp isolates from the University Hospital Cologne were examined for the presence of acquired virulence factors using whole-genome sequencing and phenotypic tests, and results were linked to clinical data. The virulence factor iuc was present in 18/109 of the CP-Kp isolates. Other acquired virulence factors, such as ybt, cbt, iro, rmpA/rmpA2, peg-344, and hypervirulence-associated capsule types were detected in various combinations among these isolates. The iuc-positive isolates produced OXA-232 (n = 7), OXA-48 (n = 6), OXA-48+NDM (n = 3), NDM, and KPC (each n = 1), and 7/18 isolates were resistant to ceftazidime-avibactam, colistin, and/or cefiderocol. Four isolates carried hybrid plasmids that harbored acquired virulence factors alongside the carbapenemase genes blaNDM-1/5 or blaOXA-48. In 15/18 patients, iuc-positive CP-Kp were isolated from a clinically manifest infection site. Among these, four patients had osteomyelitis, and four patients died from pneumonia with OXA-232-producing ST231 isolates, three of them as part of an outbreak. In conclusion, acquired virulence factors are frequently detected in various combinations in carbapenemase-producing K. pneumoniae isolates in Germany, warranting continuous monitoring of infections caused by these strains.

Impact of porin deficiency on the synergistic potential of colistin in combination with ß-lactam/ß-lactamase inhibitors against ESBL- and carbapenemase-producing Klebsiella pneumoniae.

Combinations of colistin and ß-lactam/ß-lactamase inhibitors (BLBLIs) have shown in vitro synergy against ß-lactamase-producing strains. However, data are limited and conflicting, potentially attributed to variations among the examined strains. This study investigated whether loss of porins OmpK35 and OmpK36 impacts the synergistic potential of colistin in combination with ceftazidime-avibactam or meropenem-avibactam against ß-lactamase-producing Klebsiella pneumoniae. Genetically modified strains were constructed by introducing blaCTX-M-15, blaKPC-2, and blaOXA-48 chromosomally into K. pneumoniae ATCC 35657, in which the major porin-encoding genes (ompK35, ompK36) were either intact or knocked out. The in vitro activity of colistin in combination with ceftazidime-avibactam or meropenem-avibactam was evaluated by time-lapse microscopy screening and in static time-kill experiments. The deletion of porins in the ß-lactamase-producing strains resulted in 2- to 128-fold increases in MICs for the ß-lactams and BLBLIs. The activity of avibactam was concentration-dependent, and 4- to 16-fold higher concentrations were required to achieve similar inhibition of the ß-lactamases in strains with porin loss. In the screening, synergy was observed for colistin and ceftazidime-avibactam against the CTX-M-15-producing strains and colistin and meropenem-avibactam against the KPC-2- and OXA-48-producing strains. The combination effects were less pronounced in the time-kill experiments, where synergy was rarely detected. No apparent associations were found between the loss of OmpK35 and OmpK36 and combination effects with colistin and BLBLIs, indicating that additional factors determine the synergistic potential of such combinations.

Bacteriophage P2-71: a promising therapeutic against multidrug-resistant Proteus mirabilis in urinary tract infections.

Background: Proteus mirabilis is a Gram-negative, rod-shaped bacterium widely found in natural environments. It is known for causing a range of severe illnesses in mammals, particularly urinary tract infections (UTIs). This study evaluates the therapeutic efficacy of phage P2-71 against Proteus mirabilis in vivo and in vitro environments. Methods: The in vitro therapeutic potential of bacteriophage P2-71 was assessed through the ability of phage to kill Proteus mirabilis by using a plate counting assay, and biofilm inhibition and biofilm lysis assays using a microtitre plate method. Additionally, an in vivo UTI model in C57BL/6Jmice was developed via urethral inoculation of the bacterium. Phage therapy was administered through urethral injection over a period of 5 days. Therapeutic outcomes were measured by analyzing bacterial load, phage titer, inflammatory markers, and histopathological changes in the urine, urogenital tissues, and spleen. Results: In vitro, bacteriophage P2-71 achieved significant reductions in P. mirabilis concentrations, with log reductions of 1.537 and 0.7009 CFU/mL in laboratory and urine environments, respectively (p < 0.001). The phage also decreased biofilm formation by 34-49% and lysed 15-25% of mature biofilms at various multiplicities of infection (MOIs) (p < 0.001). In vivo, phage treatment significantly lowered bacterial concentrations in the urine on Days 1 and 3 (p < 0.0001), achieving a maximum reduction of 4.602 log10 CFU/mL; however, its effectiveness diminished by Day 5 (p > 0.05). Concurrently, phage titers decreased over time. Importantly, phage treatment notably reduced bacterial load in the bladder, kidneys, and spleen (p < 0.001). Inflammatory markers such as IL-6, IL-1ß, and TNF-α were significantly lower in the treatment group, especially in the bladder (p < 0.0001), indicating an effective reduction in inflammation. Histopathological analysis showed significant mitigation of tissue damage. Conclusion: The results demonstrated that bacteriophage P2-71 is a promising alternative therapy for UTIs caused by MDR Proteus mirabilis. This bacteriophage therapy offers a viable strategy for managing infections where traditional antimicrobials fail, highlighting its potential in clinical applications.

Sensitization of Multidrug Resistant Cancer Cells to Doxorubicin Using Ebselen by Disturbing Cellular Redox Status.

Multidrug resistance (MDR) poses a significant problem in cancer treatment, often causing adverse effects during chemotherapy. Ebselen (Ebs), a synthetic organoselenium compound, affects cellular redox status in cancer cells. In the study, we observed that Ebs disrupted cellular redox balance and sensitized drug-resistant cells to doxorubicin (DOX) treatment. The combination of Ebs and DOX led to increased intracellular reactive oxygen species (ROS) levels and lipid peroxidation while decreasing the activity of thioredoxin reductase (TrxR) and cellular antioxidants in drug-resistant cells. Furthermore, this combination treatment demonstrated notable chemosensitizing effects by reducing cell viability and proliferation in MDR cells compared to DOX treatment alone. Additionally, the combination of Ebs and DOX induced DNA fragmentation and exhibited G2/M phase cell cycle arrest. Immunofluorescent analysis revealed that the Ebs and DOX combination upregulated the expression of p53 and p21, which activated the mitochondrial-dependent apoptotic pathway. The combination treatment also enhanced the upregulation of proapoptotic markers such as Bax, Caspase-3, -9, and cytochrome C, while downregulating the expression of the antiapoptotic marker Bcl-2. Therefore, the current discoveries suggest that Ebs could be employed as a drug candidate for reversing MDR in cancer cells by regulating cellular redox homeostasis.

Draft genomes of 10 Vibrio cholerae isolates collected in Sudan in 2019.

This report presents the first genomes from positive cases of cholera in Sudan. Genomic analysis of 10 Vibrio cholerae isolates, profiled as serogroup O1, reveals evidence of antimicrobial resistance genes and a 139-kb IncC plasmid with 99.74% identity to the multidrug-resistant plasmid pCNRVC190243 previously reported in Yemen and Lebanon.

The molecular mechanisms of chemotherapeutic resistance in tumors (Review).

Chemotherapy remains a prevalent treatment for a wide range of tumors; however, the majority of patients undergoing conventional chemotherapy experience varying levels of chemoresistance, ultimately leading to suboptimal outcomes. The present article provided an in­depth review of chemotherapy resistance in tumors, emphasizing the underlying factors contributing to this resistance in tumor cells. It also explored recent advancements in the identification of key molecules and molecular mechanisms within the primary chemoresistant pathways.

Nosocomial carbapenem-drug resistant Acinetobacter baumannii, related factors and clinical outcomes in Northeast Iran.

BACKGROUND AND OBJECTIVES: Nosocomial infections, including drug-resistant Acinetobacter baumannii infections, continue to impact the health of hospitalized patients. This study sought to determine the prevalence of these infections and assess the associated risk factors and clinical outcomes in Gorgan, Iran. METHODS: A retrospective cross-sectional study was conducted on 143 infected patients with Acinetobacter baumannii in two educational hospitals in Gorgan city, Iran between 2016 and 2018. Patient information including age, gender, reason and duration of hospitalization, background of diseases, type of sample culture, symptoms, laboratory findings, prescribed antibiotics, and antibiogram were collected and analyzed. The Logistic regression and survival statistical methods were used by software of SPSS 26. RESULTS: A total of 37 patients (25.87%) died during hospitalization. The less than one year and 45-65 years age groups demonstrated more deaths (29.7%; p-value < 0.001). Being single (not being married) was found to be a risk factor in increasing the chance of death among patients (OR = 2.154, 95% CI: 1.02-4.53; p = 0.048). Hospitalization in intensive care units (ICUs) was a risk factor for the death of patients (OR = 4.655, 95% CI: 7.6-83.2). The resistance to carbapenems was reported to be an important risk factor for the death of patients. CONCLUSIONS: Acinetobacter baumannii infections, particularly those resistant to carbapenems, are a significant risk for patients in ICUs and can lead to higher mortality rates.

Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect.

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.79 vs. 64.41). Further investigation indicated that 7i dose-dependently inhibited P-gp function, without affecting its expression. CETSA results illustrated that 7i could obviously improve P-gp stability, suggesting its high affinity with P-gp. Molecular docking analysis revealed that 7i fit well into P-gp's binding pocket, thus displaying potent reversal effect on P-gp-mediated tumor MDR Optical properties evaluation confirmed that azo-containing 7i can undergo reversible changes in the cis and trans configurations under the irradiation of 365 nm and 520 nm wavelength of light. Notably, the configuration change of azo might affect the MDR-reversal potency, and cis-7i has a lower RF value than trans-7i (122.70 vs. 142.79), suggesting that development of photoswitchable P-gp inhibitors might be a novel strategy to reduce the systemic toxicity caused by indiscriminate inhibition of P-gp by traditional inhibitors. Collectively, 7i, as a novel P-gp inhibitor, warranted further investigation.

Metallo-ß-lactamase-producing Pseudomonas aeruginosa Isolates from Two Tertiary Care Centres in a District of Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Pseudomonas aeruginosa isolates producing metallo-ß-lactamase have caused nosocomial outbreaks, severe infections, and ineffective carbapenem therapy worldwide since 1991. Due to their prevalence, hospital infection control techniques are difficult. This study aimed to find out the prevalence of metallo-ß-lactamase among P. aeruginosa isolates from two tertiary care hospitals in Kathmandu. METHODS: A descriptive cross-sectional study was conducted at the Department of Microbiology and Department of Pathology of two tertiary care centres in Kathmandu from 7 December 2021 to 6 April 2023, after receiving ethical approval from the Ethical Review Board. Isolated strains were identified and tested for antibiotic susceptibility by modified Kirby-Bauer Methods. Metallo-ß-lactamase presence was confirmed using an imipenem-imipenem/ ethylenediaminetetraacetic acid disc. A convenience sampling method was used. The point estimate was calculated at 95% Confidence Interval. RESULTS: Among 255, Pseudomanas aeruginosa isolates, the distribution of metallo-ß-lactamase-producing Pseudomanas aeruginosa was 103 (40.39%) (34.32-46.69 at 95% Confidence Interval). Multidrug resistance categories included multidrug resistance 74 (71.80%), extensively drug resistance 32 (31.10%), P. aeruginosa difficult-to-treat 16 (15.53%) and carbapenem-resistant P. aeruginosa was determined to be 82 (79.60%). CONCLUSIONS: The study found a high prevalence of metallo-ß-lactamase-producing Pseudomanas aeruginosa isolates, requiring early identification, infection control measures, and an all-inclusive antimicrobial therapy protocol to reduce their spread in medical settings.

Differential Selectivity of Human and Mouse ABCC4/Abcc4 for Arsenic Metabolites.

Millions of people globally are exposed to the proven human carcinogen arsenic at unacceptable levels in drinking water. In contrast, arsenic is a poor rodent carcinogen, requiring >100-fold higher doses for tumour induction, which may be explained by toxicokinetic differences between humans and mice. The human ATP-binding cassette (ABC) transporter hABCC4 mediates the cellular efflux of a diverse array of metabolites, including the GSH conjugate of the highly toxic monomethylarsonous acid (MMAIII), MMA(GS)2, and the major human urinary arsenic metabolite dimethylarsinic acid (DMAV). Our objective was to determine if mouse Abcc4 (mAbcc4) protected against and/or transported the same arsenic species as hABCC4. The anti-ABCC4 antibody M4I-10 epitope was first mapped to an octapeptide (411HVQDFTA418F) present in both hABCC4 and mAbcc4, enabling quantification of relative amounts of hABCC4/mAbcc4. mAbcc4 expressed in HEK293 cells did not protect against any of the six arsenic species tested [arsenite, arsenate, MMAIII, monomethylarsonic acid, dimethylarsinous acid or DMAV], despite displaying remarkable resistance against the antimetabolite 6-mercaptopurine (>9-fold higher than hABCC4). Furthermore, mAbcc4-enriched membrane vesicles prepared from transfected HEK293 cells did not transport MMA(GS)2 or DMAV, despite a >3-fold higher transport activity than hABCC4-enriched vesicles for the prototypic substrate 17ß-estradiol-17-(ß-D-glucuronide). Abcc4(+/+) mouse embryonic fibroblasts (MEFs) were ~3-fold more resistant to arsenate than Abcc4(-/-) MEFs; however, further characterization indicated this was not mAbcc4 mediated. Thus, under the conditions tested, arsenicals are not transported by mAbcc4, and differences between the substrate selectivity of hABCC4 and mAbcc4 seem likely to contribute to differences in human and mouse arsenic toxicokinetics. Significance Statement Toxicokinetics of the carcinogen arsenic differ among animal species. Arsenic methylation is known to contribute to this, whereas arsenic transporters have not been considered. The human ATP-binding cassette transporter hABCC4 is a high affinity transporter of toxicologically important arsenic metabolites. Here we used multiple cell models to demonstrate that mouse Abcc4 does not protect cells against, or transport, any arsenic species tested. Thus, differences between hABCC4 and mAbcc4 substrate selectivity likely contribute to differences in human and mouse arsenic toxicokinetics.

Atypical Multidrug-Resistant Salmonella paratyphi B Infection in a Patient with Uncontrolled Diabetes Mellitus: A Case Report.

Atypical Salmonella infection usually presents with unusual symptoms in addition to gastroenteritis. Such atypical presentations can pose a challenge for diagnosis and treatment as they may be misdiagnosed, leading to delayed care and potential complications. Here we report an unusual case of Salmonella spp. isolated from a wound swab. A 57-year-old male patient with a history of uncontrolled type 2 diabetes presented to the general surgery department with a 25-day history of swelling, ulceration, and purulent discharge on his right foot. A wound swab was collected for culture and sensitivity. Gram staining showed occasional pus cells and a few gram-negative bacilli. Culture was done, and the organism was identified as Salmonella Paratyphi B with the help of other biochemicals. The isolate showed susceptibility to chloramphenicol and cotrimoxazole and resistance to other panels of antibiotics. Routine blood and urine analysis of the patient showed normal findings. Wound dressing was done on an alternative day, followed by administration of antibiotics. The patient was advised to follow up after two weeks. The clinical outcome in the above patient was satisfactory with appropriate antibiotics. We present a case of atypical typhoidal Salmonella as a rare cause of wound infection and not a major threat if diagnosed and treated accordingly.

Promising New Targets for the Treatment of Infections Caused by Acinetobacter baumannii: A Review.

Acinetobacter baumannii is a globally disseminated Gram-negative bacterium that causes several types of serious nosocomial infections, the most worrisome being ventilator-associated pneumonia and bacteremia related to using venous catheters. Due to its great ability to form biofilms, combined with its survival for prolonged periods on abiotic surfaces and its potential to acquire and control the genes that determine antibiotic resistance, A. baumannii is at the top of the World Health Organization's priority list of pathogens in urgent need of new therapies. In this sense, this review aimed to present and discuss new molecular targets present in A. baumannii with potential for promising treatment approaches. This review highlights crucial molecular targets, including cell division proteins, membrane synthesis enzymes, and biofilm-associated components, offering promising targets for novel antimicrobial drug development against A. baumannii infections.

Impact of untreated tannery wastewater in the evolution of multidrug-resistant bacteria in Bangladesh.

The tannery industry produces one of the worst contaminants, and unsafe disposal in nearby waterbodies and landfills has become an imminent threat to public health, especially when the resulting multidrug-resistant bacteria and heavy metals enter community settings and animal food chains. In this study, we have collected 10 tannery wastewater (TWW) samples and 10 additional non-tannery wastewater (NTW) samples to compare the chemical oxygen demand (COD), pH, biological oxygen demand (BOD), dissolved oxygen (DO), total dissolved solids (TDS), chromium concentration, bacterial load, and antibiotic resistance profiles. While COD, pH, and chromium concentration data were previously published from our lab, this part of the study uncovers that TWW samples had a significantly higher bacterial load, compared to the non-tannery wastewater samples (5.89 × 104 and 9.38 × 103 cfu/mL, respectively), higher BOD and TDS values, and significantly lower DO values. The results showed that 53.4, 46.7, 40.0, and 40.0% of the TWW isolates were resistant to ceftriaxone, erythromycin, nalidixic acid, and azithromycin, respectively. On the other hand, 20.0, 30.0, 50.0, and 40.0% of the NTW isolates were resistant to the same antibiotics, respectively. These findings suggest that the TWW isolates were more resistant to antibiotics than the NTW isolates. Moreover, the TWW isolates exhibited higher multidrug resistance than the NTW isolates, 33.33, and 20.00%, respectively. Furthermore, spearman correlation analysis depicts that there is a negative correlation between BOD and bacterial load up to a certain level (r = - 0.7749, p = 0.0085). In addition, there is also a consistent negative correlation between COD and bacterial load (r = - 0.7112, p = 0.0252) and TDS and bacterial load (r = - 0.7621, p = 0.0104). These findings suggest that TWW could pose a significant risk to public health and the environment and highlight the importance of proper wastewater treatment in tannery industries.

Phenotypic and Genotypic of Antimicrobial Resistance Profile of Staphylococcus Spp. Isolated from Raw Milk and Artisanal Cheese.

Staphylococcus aureus and a few species of coagulase negative are frequently associated with food poisoning. Raw milk and dairy products are among the foods usually associated with outbreaks due to staphylococcal intoxication. This study aimed to determine phenotypic and genotypic antimicrobial resistance profiles to beta-lactam drugs in Staphylococcus coagulase positive (CoPS) and negative (CoNS) isolates. A total of 58 CoPS and 45 CoNS isolates recovered from raw milk and artisanal cheese from Santa Catarina were analyzed. All isolates (n = 103) were subjected to antimicrobial susceptibility testing. High levels of resistance to penicillin (41% of CoPS and 31% of CoNS), amoxicillin (40% CoPS), ampicillin (36% CoPS), and sulfamethoxazole-trimethoprim (35% CoNS) were observed. Twenty six percent of the isolates (18 CoPS and 9 CoNS) exhibited multiresistance profile; which means, they were resistant to at least three different classes of the antimicrobial drugs. Detection of resistance genes (mecA, mecC, and blaZ) was performed using multiplex polymerase chain reaction. Twelve isolates (9 CoPS and 3 CoNS) were positive for mecA, whereas 10 strains (4 CoPS and 6 CoNS) were positive for blaZ. The detection of resistant and multidrug resistant isolates emphasizes the necessity to develop strategies to better comply with good manufacturing practices and health care guidelines.