HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes.
Antimicrobial resistant (AMR) infections pose a serious risk to human and animal health. The main factors that contribute to this global crisis is shared resistance genes between different bacteria via plasmids. WHO list of Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae producing extended-spectrum β-lactamase (ESBL) and carbapenemases as “critical” priority to the development of new drugs. These resistance genes are most commonly shared via plasmid transfer.
However, finding a method to prevent the sharing of resistance genes has been hampered by the lack of filtration systems for medium / high-throughput approaches. Here, we have used plasmid ESBL-producing, PCT, and plasmid carbapenemase-producing, pKpQIL, two Gram-negative bacteria are different, E. coli and K. pneumoniae resistance By using a combination of pathogens is important, we developed an assay using a protein fluorescent, flow cytometry and confocal microscopy to assess inhibition of transmission of plasmids in bacterial populations in medium-throughput way. Three compounds with some reports of properties antiplasmid tested; chlorpromazine reduce transmission of both plasmid and linoleic acid reduces the transmission of PCT.
We screened Prestwick library of more than 1,200 FDA-approved drugs / compounds. From this, we found two NRTI drugs used to treat HIV, abacavir and azidothymidine (AZT), which reduces the transmission of plasmids (AZT, for example, at 0.25 ug / ml reduces the transmission of PCT in E. coli by 83.3% and transmission pKpQIL in K. pneumoniae by 80.8% compared to untreated controls). transmission plasmid reduced drug concentration under peak serum concentrations and can be achieved in the digestive tract.
These drugs can be used to decolonize humans, animals or the environment from AMR plasmids.IMPORTANCE infection more bacteria are becoming resistant to antibiotics. This has made the treatment of many infections are very difficult. One of the reasons this is such a big problem is that the bacteria can share their genetic material with other bacteria, and these genes together often include resistance to various antibiotics, including several of our drug last.
We addressed this problem by using a fluorescence-based systems for medicine that will stop the bacteria from sharing the resistance gene. We discovered a new role for the two drugs used to treat HIV and demonstrate that they are capable of preventing the sharing of two types of resistance genes in two strains of bacteria that are unique. This work laid the foundation for future work to reduce the prevalence of resistant infections.
HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes.
screening compounds in a cell-based model of the formation of tau inclusions: Comparison of primary neurons and HEK293 cell assays.
he Hallmark pathological features of Alzheimer’s disease (AD) brain senile plaques, composed of amyloid β (Aβ) peptides and nerve inclusions formed from protein tau. This plaque forming 10-20 years before the onset of AD symptoms, whereas robust tau pathology associated more closely with the symptoms and correlated with cognitive status.
The temporal sequence of the development of AD pathology, coupled with repeated clinical failures Aβ-directed drug, indicating that the molecule that reduce tau inclusions have therapeutic potential. Some tau-directed drug is currently in clinical trials, partly because of the difficulty in identifying molecules that reduce tau inclusions.
We describe here two cell based assays inclusion establishment know that we are used to screen for compounds that inhibit tau pathology; HEK293 cell-based assay tau excess and primary rat cortical neurons with physiological tau expression assay. Screening the collection ~ 3500 pharmaceutical compounds with tau aggregation test HEK293 cells, we obtained only a low number of hit compounds.
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In addition, these compounds have generally failed to inhibit the formation of tau inclusions in test cortical neurons.
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