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Anti-Mycobacterial Drug Resistance in Japan: How to Approach This Problem?

ABSTRACT: Mycobacteriosis is mainly caused by two groups of species: Mycobacterium tuberculosis and non-tuberculosis mycobacteria (NTM). The pathogens cause not only respiratory infections, but also general diseases. The common problem in these pathogens as of today is drug resistance. Tuberculosis (TB) is a major public health concern. A major challenge in the treatment of TB is anti-mycobacterial drug resistance (AMR), including multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Recently, the success rate of the treatment of drug-resistant tuberculosis (DR-TB) has improved significantly with the introduction of new and repurposed drugs, especially in industrialized countries such as Japan. However, long-term treatment and the adverse events associated with the treatment of DR-TB are still problematic. To solve these problems, optimal treatment regimens designed/tailor-made for each patient are necessary, regardless of the location in the world. In contrast to TB, NTM infections are environmentally oriented. Mycobacterium avium-intracellulare complex (MAC) and Mycobacterium abscessus species (MABS) are the major causes of NTM infections in Japan. These bacteria are naturally resistant to a wide variation of antimicrobial agents. Macrolides, represented by clarithromycin (CLR) and amikacin (AMK), show relatively good correlation with treatment success. However, the efficacies of potential drugs for the treatment of macrolide-resistant MAC and MABS are currently under evaluation. Thus, it is particularly difficult to construct an effective treatment regimen for macrolide-resistant MAC and MABS. AMR in NTM infections are rather serious in Japan, even when compared with challenges associated with DR-TB. Given the AMR problems in TB and NTM, the appropriate use of drugs based on accurate drug susceptibility testing and the development of new compounds/regimens that are strongly bactericidal in a short-time course will be highly expected.

SUBMITTER: Kamada K

PROVIDER: S-EPMC8773147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We used all five current human African trypanosomiasis drugs for genome-scale RNA interference (RNAi) target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the transporters, organelles, enzymes and metabolic pathways that function to facilitate anti-trypanosomal drug action. RIT-seq profiling links more than fifty additional genes to drug action. This data has been described in the following article [doi:10.1038/nature10771] and its further analysis can be freely submitted for publication. For information on the proper use of data shared by the Wellcome Trust Sanger Institute (including information on acknowledgement), please see http://www.sanger.ac.uk/datasharing/. Protocol - Assembly of the bloodstream-form T. brucei RNAi library and the RNAi target sequencing (RIT-seq) approach were reported previously (Alsford, S. et al. High-throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Genome Res 21, 915-924, 264 doi:gr.115089.110 [pii] 265 10.1101/gr.115089.110 (2011). Briefly, a tetracycline-inducible RNAi plasmid library, containing randomly sheared genomic fragments (mean ~600 bp) under the control of head-to-head T7 promoters, was targeted to a single genomic locus that had been validated for robust expression. For this study, the library was grown under inducing conditions with drug selection and genomic DNA was isolated from surviving populations. For chemical RIT-seq profiling, adapter-ligated sequencing libraries were prepared from each genomic DNA sample and used to amplify DNA fragments containing RNAi cassette-insert junctions in semi-specific PCR reactions; one primer was specific for the RNAi vector and the other for the Illumina adapter. Size-selected DNA was sequenced with 76 cycle paired-end runs on an Illumina GAII. Illumina sequencing reads containing a nine-base RNAi vector junction sequence were then mapped to the T. brucei reference genome. Where loss of function increases drug tolerance, RNAi-target sequence representation is increased relative to the otherwise susceptible population, revealing hot spots.

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Anti-Mycobacterial Drug Resistance in Japan: How to Approach This Problem?

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