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Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.

Broad-spectrum resistance in cancer cells is often caused by the overexpression of ABC transporters; which varies across individuals because of genetic single-nucleotide polymorphisms (SNPs). In the present study; we focused on human ABCC4 and established cells expressing the wild-type (WT) or SNP variants of human ABCC4 using the Flp-In™ system (Invitrogen, Life Technologies Corp, Carlsbad, CA, USA) based on Flp recombinase-mediated transfection to quantitatively evaluate the effects of nonsynonymous SNPs on the drug resistance profiles of cells. The mRNA levels of the cells expressing each ABCC4 variant were comparable. 3-(4,5-Dimethyl-2-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay clearly indicated that the EC50 values of azathioprine against cells expressing ABCC4 (WT) were 1.4–1.7-fold higher than those against cells expressing SNP variants of ABCC4 (M184K; N297S; K304N or E757K). EC50 values of 6-mercaptopurine or 7-Ethyl-10-hydroxy-camptothecin (SN-38) against cells expressing ABCC4 (WT) were also 1.4–2.0- or 1.9-fold higher than those against cells expressing the SNP variants of ABCC4 (K304N or E757K) or (K304N; P403L or E757K); respectively. These results indicate that the effects of nonsynonymous SNPs on the drug resistance profiles of cells expressing ABCC4 can be quantitatively evaluated using the Flp-In™ system.

Vibrio parahaemolyticus is a significant causal agent of acute hepatopancreatic necrosis disease (AHPND), with huge production losses of white leg shrimp, Litopenaeus vannamei, cultivated globally, including aquaculture farms in the Mekong Delta of Vietnam. Controlling this disease is critical because of the worldwide expansion of antimicrobial‐resistant V. parahaemolyticus isolates. The purpose of this study was to determine the frequency of multi‐antibiotic resistance (MAR) in V. parahaemolyticus isolated from AHPND white leg shrimp extensively cultivated in Bac Lieu Province (Mekong Delta). Based on biochemical tests and toxR‐PCR positive detections, 34 V. parahaemolyticus isolates were identified. Antibiotic susceptibility examination revealed that most of the isolates were phenotypically multidrug resistant, including resistance to ceftazidime (100%) and amoxicillin (97.06%), followed by colistin (74%) and erythromycin (65%). These isolates were highly sensitive to doxycycline (94%), followed by florfenicol (74%) and flumequine (71%). There were 27 distinct MAR phenotypes detected among 34 isolates, with 14.71% of the isolates exhibiting the antibiotic profile AMO‐CEF‐CEP‐COL‐ERY, followed by 11.76% for each of the profiles AMO‐CEP‐TET‐COL and AMO–CEP–COL. In particular, 25 isolates (75%) were resistant to at least 5 (of the 12) antibiotics tested. A hierarchical clustering analysis of antibiotic‐resistant V. parahaemolyticus isolates indicated cross‐transmission across farms and its ability to survive in aquatic environments for extended periods (over 3 months). Our findings support the hypothesis that the variety of MARPs in V. parahaemolyticus is the result of human activities. Environmentally friendly therapy strategies should be used for the prophylaxis and treatment of V. parahaemolyticus infection.

The aims of this study were to characterize and investigate antimicrobial susceptibility and presence of integrons in 161 Aeromonas spp. isolated from ornamental freshwater fish farming environment, apparently healthy and diseased fish. Phylogenetic analyses of the gyrB gene sequences identified Aeromonas veronii as the most abundant species (75.8%) followed by Aeromonashydrophila (9.3%), Aeromonas caviae (5%), Aeromonas jandaei (4.3%), Aeromonas dhakensis (3.7%), Aeromonas sobria (0.6%), Aeromonas media (0.6%), and Aeromonas popoffii (0.6%). Susceptibility to thirteen antimicrobials was determined and antimicrobial resistance frequencies were: amoxicillin (92.5%), enrofloxacin (67.1%), nalidixic acid (63.4%), erythromycin (26.1%), tetracycline (23.6%), imipenem (18%), trimethoprim-sulfamethoxazole (16.8%), and gentamicin (16.8%). Multi-drug resistance (MDR) was widespread among the isolates (51.6%, 83/161) with 51.6% (63/122) A. veronii isolates being MDR. In addition, 68.3% of isolates had multiple antibiotic resistance (MAR) indexes higher than 0.2, suggesting that they originated from a high-risk source of contamination where antimicrobials are often used. In all, 21.7% isolates carried class 1 integrons, with 97.1% having gene cassettes, while there were 12 isolates carrying class 2 integron gene cassettes. Our findings highlight that the aquatic environment and ornamental fish act as reservoirs of multidrug resistant Aeromonas spp. and underline the need for a judicious use of antimicrobials and timely surveillance of antimicrobial resistance (AMR) in aquaculture.

Multi‐drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH‐sensitive photosensitizer‐drug conjugates (CyR‐SS‐L) are designed and synthesized. CyR‐SS‐L localized in the mitochondria then is cleaved into CyR‐SG and SG‐L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR‐SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG‐L part is used for chemotherapy. CyR‐SS‐L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR‐SS‐L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy. A glutathione‐sensitive photosensitizer‐drug is firsted designed to simultaneously realize tumor photodynamic therapy and chemotherapy. The disulfide linkage in predrug is broken by glutathione reductase, releasing active photosensitizers and Lonidamine. Due to the synergistic effect, the expression of ATP‐binding cassette subfamily B member 1 (ABCB1) is reduced and the drug resistance pathway is broken, resulting to the efficient cancer treatment.

Sputum culture conversion status is a cardinal index of treatment response and patient outcome for MDR TB patients on longer anti-TB drugs. But, there is limited information on time to sputum culture conversion of MDR TB patients on a longer anti-TB treatment regimen. Therefore, this study aimed to evaluate time to sputum culture conversion and its predictors among MDR TB patients in Tigray, Northern Ethiopia. A retrospective cohort study was conducted from January 2017 through September 2020 among MDR TB patients in Tigray, Northern Ethiopia. Demographic and clinical characteristics including bacteriological data were extracted from the TB registration book and electronic database in Tigray Health Research Institute. Statistical analysis was performed using SPSS version 25. The time to initial sputum culture conversion was analyzed using the Kaplan-Meier method. Bivariate and multivariate Cox proportional hazards regression analyses were used to identify predictors for culture conversions. P <0.05 was considered statistically significant. A total of 294 eligible study participants with a median age of 30 years (IQR: 22.75-40) were included. The participants were followed for a total of 1066.7 person months. Sputum culture conversion was achieved in 269 (91%) of the study participants. The median time of sputum culture conversion was 64 days (IQR: 49-86). In our multivariate model, HIV-positive (aHR=1.529, 95% CI: 1.096-2.132, P=0.012), patients new to anti-TB treatment (aHR=2.093, 95% CI: 1.100-3.982, P=0.024) and baseline AFB smear grading of +1 (aHR=1.982, 95% CI: 1.428-2.750, P=0.001) significantly affected time to initial sputum culture conversion. The median time of culture conversion was 64 days. Moreover, the majority of the study participants achieved culture conversion within the first six months of treatment commencement, which supports predefined standard treatment durations.

The continuous emergence of multidrug‐resistant bacterial pathogens poses a major global healthcare challenge, with Klebsiella pneumoniae being a prominent threat. We conducted a comprehensive study on K. pneumoniae’s antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last‐resort antibiotic. Our research demonstrates that OMVs protect bacteria from polymyxins. OMVs derived from Polymyxin B (PB)‐stressed K. pneumoniae exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed Klebsiella. OMVs also shield bacteria from different bacterial families. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and Galleria mellonella. In all models, OMVs protected K. pneumoniae from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. The altered binding capacity of single OMVs from PB stressed K. pneumoniae could be linked to a reduction in the lipid A amount of their released vesicles. Although the amount of lipid A per vesicle is reduced, the overall increase in the number of vesicles results in an increased protection because the sum of lipid A and therefore PB binding sites have increased. This unravels the mechanism of the altered PB protective efficacy of OMVs from PB stressed K. pneumoniae compared to control OMVs. The lipid A‐dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected Klebsiella from PB ex vivo and in vivo. The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross‐protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug‐resistant bacterial infections.

Streptococcus agalactiae is a zoonotic human and animal pathogen that causes global economic losses in aquaculture and fatal outcomes in Tilapia. This study aimed to identify S. agalactiae isolated from different fish sources intended for human consumption phenotypically and genotypically and to characterize the virulence-associated genes (fibrinogen-binding protein FbsA), cfb (CAMP factor), and pbp1A/ponA (penicillin-binding protein 1A). Three hundred Nile Tilapia fish ( ) were collected from different farms and retail shops in Dakahlia and Damietta, Egypt, during the summer of 2020. The samples were examined using routine phenotypic methods, then characterized using polymerase chain reaction (PCR) targeting -specific gene. All S. agalactiae isolates were examined for the susceptibility to ten antimicrobial agents by the disc diffusion method. The virulence-associated genes (fbsA, cfb, and pbp1A/ponA) were characterized using multiplex-PCR. Streptococcus agalactiae was detected in 7% ( = 21/300) samples. The isolates showed high resistance against ampicillin and erythromycin (20/21; 95%) for each. The most predominant antibiotypes through isolates were P, CN, SXT, CRO, TE, CTX, E, AMP, at 10.5% for each antibiotype. A total of 19 (90.5%) of S. agalactiae isolates showed multi-drug resistance (MDR), and those were recovered from market Tilapia fish. The virulence-associated genes (fbsA, cfb, and pbp1A/ponA) were identified in the S. agalactiae as 100%, 76%, and 52%, respectively. The MDR S. agalactiae detected in raw Tilapia fish pose a significant health hazard to consumers due to their zoonotic characteristics.

Gram-positive cocci are clinically important pathogens that cause infections and their development of antibiotic resistance continues to pose a severe threat to public health. Therefore, this study aims to investigate the level of antimicrobial resistance among Gram-positive cocci isolated from different clinical samples among patients referred to Arsho Advanced Medical Laboratory, Addis Ababa, Ethiopia. From January to April 2018, a cross-sectional study was conducted at Arsho Advanced Medical Laboratory. Seven hundred ninety-two (792) different clinical samples were obtained from 792 individuals and inoculated into blood culture bottles and Blood Agar base. Bacterial identification was done using the number, type, and morphology of colonies, as well as Gram staining, catalase testing, and coagulase test after isolation of pure growth on culture media using the standard operating procedure. VITEK 2 compact system was used for bacterial identification and drug susceptibility testing. The information entry and analysis were performed by using SPSS version 20. Out of 792 clinical samples cultured, the prevalence of Gram-positive cocci was 12.6% (n=100/792). The most frequent one is 54% (n=54/100) followed by coagulase-negative species 42% (n=42/100), 1% (n=1/100) and 3% (n=3/100). Penicillin showed the highest resistance rate 85% (n=85/100), followed by sulfamethoxazole/trimethoprim (47%), and oxacillin (38%); however, highest sensitivity was seen towards linezolid 97% (n=97/100) and vancomycin 94% (n=94/100). The total multi-drug resistance (MDR) Gram-positive cocci were 44% (n=44/100). This study demonstrated high antimicrobial resistance and multi-drug resistance. This suggests that the importance of continuous monitoring of antimicrobial resistance patterns is crucial for selecting the suitable drug for treatment and infection prevention.

•  Introduction •  The caveolins •  Caveolin‐1 in cell physiology ‐  Caveolin‐1 distribution ‐  Caveolin‐1 and internalization ‐  Caveolin‐1 and cholesterol ‐  Regulation of caveolin‐1 expression ‐  Caveolin‐1 in signal transduction ‐  Alternative mechanisms of caveolin‐1‐mediated control in signalling ‐  Control of transcription ‐  Other modes of control ‐  Cell proliferation ‐  Cell death and apoptosis •  Caveolin‐1 in cancer ‐  The tumour suppressor hypothesis ‐  Caveolin‐1 in multi‐drug resistance and metastasis •  Concluding remarks Caveolae are small plasma membrane invaginations that have been implicated in a variety of functions including transcytosis, potocytosis and cholesterol transport and signal transduction. The major protein component of this compartment is a family of proteins called caveolins. Experimental data obtained in knockout mice have provided unequivocal evidence for a requirement of caveolins to generate morphologically detectable caveolae structures. However, expression of caveolins is not sufficient per seto assure the presence of these structures. With respect to other roles attributed to caveolins in the regulation of cellular function, insights are even less clear. Here we will consider, more specifically, the data concerning the ambiguous roles ascribed to caveolin‐1 in signal transduction and cancer. In particular, evidence indicating that caveolin‐1 function is cell context dependent will be discussed.