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Journal of Nepal Health Research Council Mar 2022Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen frequently causing healthcare-associated infections. The apocalyptic rise of antimicrobial resistance...
BACKGROUND
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen frequently causing healthcare-associated infections. The apocalyptic rise of antimicrobial resistance has rekindled interest in age-old phage therapy that uses phages (viruses that infect bacteria) to kill the targeted pathogenic bacteria. Because of its specificity, phages are often considered as potential personalized therapeutic candidate for treating bacterial infections.
METHODS
In this study, we isolated and purified lytic phages against multi-drug resistant P. aeruginosa using soft agar overlay technique. Phage characteristics like thermal and pH stability, latent period and burst size were determined using one-step growth assay while multiple host range spectrum was determined by spot assay. The phages were further characterized using protein profiling.
RESULTS
Three Pseudomonas phages (øCDBT-PA31, øCDBT-PA56 and øCDBT-PA58) were isolated from the holy rivers of Kathmandu valley. Among 3 phages, øCDBT-PA31 demonstrated multiple host range and could lyse multi-drug resistant strain of P. aeruginosa. Further, øCDBT-PA31 showed latent period of 30 minutes with corresponding burst sizes of 423-525 PFU/cell. Interestingly, øCDBT-PA31 also tolerated a wide range of adverse conditions, such as high temperature (50°C) and pH 3-11. Further, protein profiling revealed that øCDBT-PA31 has 4 and øCDBT-PA11 had 3 distinct bands in the gradient gel ranging from approximately 3.5-29 kilodaltons (kDa) suggesting them to be morphologically distinct from each other.
CONCLUSIONS
As multi-drug resistant bacteria are emerging as a global problem, lytic phages can be an alternative treatment strategy when all available antibiotics fail.
Topics: Bacteriophages; Drug Resistance, Multiple, Bacterial; Humans; Nepal; Pseudomonas Phages; Pseudomonas aeruginosa
PubMed: 35615828
DOI: 10.33314/jnhrc.v19i04.3837 -
Biomaterials Mar 2021High intracellular glutathione (GSH) levels play an important role in multidrug resistance (MDR) in cancer cells. It remains challenging to develop a drug delivery...
High intracellular glutathione (GSH) levels play an important role in multidrug resistance (MDR) in cancer cells. It remains challenging to develop a drug delivery system that is simultaneously capable of GSH depletion and drug activation for multidrug resistance reversal. Herein, we designed a polyprodrug (denoted as PSSD) based on poly(disulfide) conjugated with doxorubicin (DOX) on the polymer side chains that exhibits GSH depletion and cascade DOX activation for drug resistance reversal. The poly(disulfide) backbone with a high disulfide density depletes intracellular antioxidant GSH via the disulfide-thiol exchange reaction to disrupt intracellular redox homeostasis in cells. Simultaneously, DOX can be activated through a cascade reaction, and degradation of the poly(disulfide) backbone further facilitates its drug release. Therefore, poly(disulfide) can be used as a GSH scavenger to reverse MDR as well as a prodrug backbone to target high intracellular GSH levels in cancer cells, providing a general strategy for drug resistance reversal.
Topics: Activation, Metabolic; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glutathione
PubMed: 33588139
DOI: 10.1016/j.biomaterials.2020.120649 -
Natural Product Reports Apr 2019Covering: 2000 to 2018, particularly from 2010 to early 2018 The increase in the incidence of antibiotic resistant infections is threatening to overwhelm healthcare... (Review)
Review
Covering: 2000 to 2018, particularly from 2010 to early 2018 The increase in the incidence of antibiotic resistant infections is threatening to overwhelm healthcare practices worldwide. Most antibiotics in clinical use are becoming ineffective, so therefore it is imperative to develop new antibiotics and novel therapeutic strategies. Traditionally, the chemical and mechanistic diversity of nonribosomal antibacterial peptides (NRAPs) as lead compounds have meant that their structures are ideal for antibiotic discovery. Here, we summarize the state of our current knowledge about the mechanisms of antibiotic resistance, which can be used to guide the development of new antibiotics. Furthermore, we provide an overview of NRAPs for treating multi-drug resistant bacteria, including innovative approaches for screening NRAPs from new sources and the underlying mechanisms of antibacterial activity. Finally, we discuss the design of NRAP scaffolds for precise medicine and combinatorial NRAP therapies with existing antibiotics to overcome resistance, which will help to control infections in the post-antibiotic era.
Topics: Anti-Bacterial Agents; Calcium; Cell Membrane; Cell Wall; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Genomics; Peptides; Proteomics; Structure-Activity Relationship
PubMed: 30324212
DOI: 10.1039/c8np00031j -
Drug Resistance Updates : Reviews and... Mar 2017Staphylococcus aureus is a major cause of bacterial infection in humans, and has been notoriously able to acquire resistance to a variety of antibiotics. An example is... (Review)
Review
Staphylococcus aureus is a major cause of bacterial infection in humans, and has been notoriously able to acquire resistance to a variety of antibiotics. An example is methicillin-resistant S. aureus (MRSA), which despite having been initially associated with clinical settings, now is one of the key causative agents of community-acquired infections. Antibiotic resistance in S. aureus involves mechanisms ranging from drug efflux to increased expression or mutation of target proteins, and this has required innovative approaches to develop novel treatment methodologies. This review provides an overview of the major mechanisms of antibiotic resistance developed by S. aureus, and describes the emerging alternatives being sought to circumvent infection and proliferation, including new generations of classic antibiotics, synergistic approaches, antibodies, and targeting of virulence factors.
Topics: Animals; Anti-Bacterial Agents; Cell Wall; Community-Acquired Infections; Drug Discovery; Drug Resistance, Multiple, Bacterial; Humans; Mutation; Penicillin-Binding Proteins; Staphylococcal Infections; Staphylococcus aureus
PubMed: 28867240
DOI: 10.1016/j.drup.2017.03.001 -
Daru : Journal of Faculty of Pharmacy,... Jun 2020Infectious diseases associated with intracellular bacteria such as Staphylococcus aureus, Salmonella typhimurium and Mycobacterium tuberculosis are important public... (Review)
Review
INTRODUCTION
Infectious diseases associated with intracellular bacteria such as Staphylococcus aureus, Salmonella typhimurium and Mycobacterium tuberculosis are important public health concern. Emergence of multi and extensively drug-resistant bacterial strains have made it even more obstinate to offset such infections. Bacteria residing within intracellular compartments provide additional barriers to effective treatment.
METHOD
Information provided in this review has been collected by accessing various electronic databases including Google scholar, Web of science, Scopus, and Nature index. Search was performed using keywords nanoparticles, intracellular targeting, multidrug resistance, Staphylococcus aureus; Salmonella typhimurium; Mycobacterium tuberculosis. Information gathered was categorized into three major sections as 'Intracellular targeting of Staphylococcus aureus, Intracellular targeting of Salmonella typhimurium and Intracellular targeting of Mycobacterium tuberculosis' using variety of nanocarrier systems.
RESULTS
Conventional management for infectious diseases typically comprises of long-term treatment with a combination of antibiotics, which may lead to side effects and decreased patient compliance. A wide range of multi-functionalized nanocarrier systems have been studied for delivery of drugs within cellular compartments where bacteria including Staphylococcus aureus, Salmonella typhimurium and Mycobacterium tuberculosis reside. Such carrier systems along with targeted delivery have been utilized for sustained and controlled delivery of drugs. These strategies have been found useful in overcoming the drawbacks of conventional treatments including multi-drug resistance.
CONCLUSION
Development of multi-functional nanocargoes encapsulating antibiotics that are proficient in targeting and releasing drug into infected reservoirs seems to be a promising strategy to circumvent the challenge of multidrug resistance. Graphical abstract.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Carriers; Drug Resistance, Multiple, Bacterial; Humans; Nanoparticles
PubMed: 32193748
DOI: 10.1007/s40199-020-00337-w -
Experimental and Molecular Pathology Feb 2021Recent understanding of different molecular aspects of tumor initiation and progression has led to the discovery of a growing list of drugs. While these drugs have shown... (Review)
Review
Recent understanding of different molecular aspects of tumor initiation and progression has led to the discovery of a growing list of drugs. While these drugs have shown promising effects on tumor cells, their widespread usage has been hampered by the acquisition of drug resistance in a subpopulation of tumor cells. A differential pattern in the secretion of specialized vesicles named "exosomes" in drug-resistant cancer cells have recently received much attention. In addition, microRNAs (miRNAs) have been shown to be enriched in exosomes. Exosomal miRNAs (also known as exo-miRs) could be shuttled to recipient cells and play a role in the regulation of post-transcriptional gene expression, which may exert certain effects on cancer drug resistance. Here, we have reviewed the role of exo-miRs in chemotherapeutic resistance in different cancer types. Besides, studies which have focused on predictive role of circulating exo-miRs in cancer drug resistance are reviewed.
Topics: Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Exosomes; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Tumor Microenvironment
PubMed: 33296693
DOI: 10.1016/j.yexmp.2020.104592 -
Viruses Sep 2021The emergence of multi-drug resistant (MDR) bacteria is recognised today as one of the greatest challenges to public health. As traditional antimicrobials are becoming... (Review)
Review
The emergence of multi-drug resistant (MDR) bacteria is recognised today as one of the greatest challenges to public health. As traditional antimicrobials are becoming ineffective and research into new antibiotics is diminishing, a number of alternative treatments for MDR bacteria have been receiving greater attention. Bacteriophage therapies are being revisited and present a promising opportunity to reduce the burden of bacterial infection in this post-antibiotic era. This review focuses on the current evidence supporting bacteriophage therapy against prevalent or emerging multi-drug resistant bacterial pathogens in respiratory medicine and the challenges ahead in preclinical data generation. Starting with efforts to improve delivery of bacteriophages to the lung surface, the current developments in animal models for relevant efficacy data on respiratory infections are discussed before finishing with a summary of findings from the select human trials performed to date.
Topics: Animals; Bacterial Infections; Bacteriophages; Clinical Trials as Topic; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Humans; Lung; Mice; Phage Therapy; Respiratory Tract Infections
PubMed: 34578390
DOI: 10.3390/v13091809 -
Acta Paediatrica (Oslo, Norway : 1992) Jun 2021This study assessed the Streptococcus pneumoniae colonisation rate and susceptibility to antibiotics among preschool children in rural Vietnam.
AIM
This study assessed the Streptococcus pneumoniae colonisation rate and susceptibility to antibiotics among preschool children in rural Vietnam.
METHOD
Nasopharyngeal samples were collected from 546 preschool children aged 6-59 months living in 460 households in the rural BaVi District of Hanoi and their main caregivers completed questionnaires. The samples were cultured, and the Streptococcus pneumoniae colonisation rate and antibiotic susceptibility were investigated. Resistance data from this 2014 study were compared with studies in 1999 and 2007, to identify 15-year trends, together with clinical isolates from a national surveillance system of 16 Vietnamese hospital laboratories established in 2013.
RESULTS
We found that 221/546 (40%) of the cultures were positive for Streptococcus pneumoniae. The susceptibility rates were trimethoprim-sulphamethoxazole (5%), erythromycin (8%), ciprofloxacin (12%), benzyl-penicillin (35%), tetracycline (49%), cefotaxime (55%), moxifloxacin (99%) and vancomycin (99%). All the susceptibility rates were lower in 2014 than 1999 and 2007, except tetracycline. Multi-drug resistance was 80% in 2014, compared to 60% in 2007 and 31% in 1999. Antibiotics was reported used by 191 (35%) within one month, mainly cephalosporins 86 (45%), amoxycillin/ampicillin 69 (36%) and macrolides 30 (16%).
CONCLUSION
Streptococcus pneumoniae showed remarkable high resistance to commonly used antibiotics, including cephalosporins. Multi-drug resistance rose from 31% to 80% during the 15-year study period.
Topics: Anti-Bacterial Agents; Child, Preschool; Drug Resistance, Multiple; Humans; Microbial Sensitivity Tests; Pneumococcal Infections; Streptococcus pneumoniae; Vietnam
PubMed: 33544434
DOI: 10.1111/apa.15795 -
Biomedicine & Pharmacotherapy =... Jan 2018Tetrandrine has been known in the treatment of tuberculosis, hyperglycemia, negative ionotropic and chronotropic effects on myocardium, malaria, cancer and fever since... (Review)
Review
Tetrandrine has been known in the treatment of tuberculosis, hyperglycemia, negative ionotropic and chronotropic effects on myocardium, malaria, cancer and fever since years together. It has been known that, tetrandrine could modulate multiple signaling molecules such as kinases of cell cycle and rat sarcoma (RAS) pathway along with proteins of tumor suppressor genes, autophagy related, β-catenins, caspases, and death receptors. Moreover, tetrandrine exhibited reversal of drug resistance by modulating P-glyco protein (P-gp) expression levels in different cancers which is an added advantage of this compound compared to other chemotherapy drugs. Though, bioavailability of tetrandrine is a limiting factor, the anticancer activity was observed in animal models without changing any pharmacokinetic parameters. In the present review, role of tetrandrine as kinase inhibitor, inducer of autophagy and caspase pathways and suppressor of RAS mediated cell proliferation were discussed along with inhibition of angiogenesis. It has also been discussed that how tetrandrine potentiate anticancer effect in different types of cancers by modulating multidrug resistance under in vitro and in vivo trials including the available literature on the clinical trials.
Topics: Animals; Antineoplastic Agents, Phytogenic; Autophagy; Benzylisoquinolines; Cell Line, Tumor; Clinical Trials as Topic; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Signal Transduction
PubMed: 29101806
DOI: 10.1016/j.biopha.2017.10.116 -
Expert Opinion on Drug Discovery Feb 2020: Bacteriological infections are a major risk to human health. These include all hospital and public-acquired infections. In drug discovery, rhodanines are privileged... (Review)
Review
: Bacteriological infections are a major risk to human health. These include all hospital and public-acquired infections. In drug discovery, rhodanines are privileged heterocyclic frameworks. Their derivatives possess strong anti-bacterial activity and some of them have shown potent activity against multidrug-resistant pathogens, both under and conditions. To treat multi-drug resistant pathogens, the development of novel potent drugs, with superior anti-bacterial efficacy, is paramount. One avenue which shows promise is the design and development of novel rhodanines.: This review summarizes the status on rhodanine-based derivatives and their anti-bacterial activity, based on published research over the past six years. Furthermore, to facilitate the design of novel derivatives with improved functions, their structure-activity relationships are assessed with reference to their efficacy as anti-bacterial agents and their toxicity.: The pharmacological activity of molecules bearing a rhodanine scaffold needs to be very critically assessed in spite of considerable information available from various biological evaluations. Although, some data on structure-activity relationship frameworks is available, information is not adequate to optimize the efficacy of rhodanine derivatives for different applications.
Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Drug Design; Drug Development; Drug Discovery; Drug Resistance, Multiple, Bacterial; Humans; Rhodanine; Structure-Activity Relationship
PubMed: 31777321
DOI: 10.1080/17460441.2020.1696768