A New Antisense Phosphoryl Guanidine Oligo-2 ′-O-Methylribonucleotide Penetrates Into Intracellular Mycobacteria and Suppresses Target Gene Expression
In this study, we investigated the uptake and biological effects of 2′-OMe PGO in mycobacteria. The results indicated that 2′-OMe PGO specific for the alanine dehydrogenase-encoding ald gene inhibited the growth of Mycobacterium smegmatis and downregulated ald expression at both the transcriptional and translational levels through an RNase H-independent mechanism, showing higher biological activity than its phosphorothioate oligonucleotide counterpart. Confocal microscopy revealed that the anti-ald 2′-OMe PGO was taken up by intracellular mycobacteria residing in RAW 264.7 macrophages without exerting toxic effects on eukaryotic cells, indicating that 2′-OMe PGO was able to efficiently cross two cellular membranes. In addition, 2′-OMe PGO inhibited the transcription of the target ald gene in M. smegmatis-infected macrophages. Thus, we demonstrated, for the first time, a possibility of targeting gene expression and inhibiting growth of intracellular mycobacteria by antisense oligonucleotide derivatives. Strong antisense activity and efficient uptake of the new RNA analogue, 2′-OMe PGO, by intracellular microorganisms revealed here may promote the development of novel therapeutic strategies to treat TB and prevent the emergence of drug-resistant mycobacterial strains.
ConclusionsBedaquiline showed similar efficacy and safety in Korean patients with MDR-TB, despite their advanced drug-resistance profiles, possibly due to other concomitant drugs such as linezolid.
A 25 year-old tuberculosis patient is treated at her home in Funafuti, the main island of Tuvalu in the South Pacific. Credit: UNDP Tuvalu/Aurélia Rusek.By External SourceUNITED NATIONS, Oct 17 2019 (IPS) A staggering 1.5 million people died from tuberculosis (TB) last year, the UN health agency said on Thursday, in an appeal for far greater funding and political support to eradicate the curable and preventable disease. Caused by the bacteria Mycobacterium tuberculosis, TB commonly causes persistent coughing, fatigue and weight loss. According to the World Health Organization (WHO) and its latest Global TB Report, a...
Antibiotic-loaded bone cement (ALBC) is used to deliver antimycobacterial agents into the focal lesion of musculoskeletal tuberculosis. Although kanamycin is currently used as an antimycobacterial agent for the treatment of multidrug-resistant tuberculosis, there is no information about its suitability in ALBC.
de Viedma D, Ritacco V Abstract Two Mycobacterium tuberculosis strains-M (sublineage 4.1) and Ra (sublineage 4.3)-have long prevailed in Argentina among patients with multidrug-resistant tuberculosis (MDR-TB). Recently, budget constraints have hampered the surveillance of MDR-TB transmission. Based on whole-genome sequence analysis, we used M- and Ra-specific single nucleotide polymorphisms to tailor two multiplex allele-specific PCRs, which we applied to 252 stored isolates (95% of all newly diagnosed MDR-TB cases countrywide), during 2015-2017. Compared with the latest data available (2007-2009), the M strain h...