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Alternative ribosomes and antibiotic tolerance in mycobacteria.

分枝杆菌中的替代核糖体和抗生素耐受性。

基本信息

批准号：
10165472
负责人：
Anil Kumar Ojha
金额：
$ 40.55万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2023-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165472
关键词：
Acute Address Anti-Bacterial Agents Antibiotics Antitubercular Agents Bacterial Infections Binding Chronic Clinical Complex Cryoelectron Microscopy DNA Sequence Alteration Data Development Dietary Zinc Distant Drug Controls Drug Tolerance Drug resistance Drug resistance in tuberculosis Erythromycin Etiology Extreme drug resistant tuberculosis FDA approved Future Gene Expression Genes Genetic Transcription Genus Mycobacterium Goals Growth Incidence Infection Kanamycin Lead Linezolid Literature Macrolides Mediating Multi-Drug Resistance Mycobacterium Infections Mycobacterium smegmatis Mycobacterium tuberculosis Operon Pathogenesis Pharmaceutical Preparations Phase Phenotype Proteins Publishing Regimen Repression Resolution Ribosomal Proteins Ribosomes Role Starvation Streptomycin Structure Testing Tuberculosis Work Zinc antibiotic tolerance base cell growth chronic infection clinically relevant design drug synthesis extensive drug resistance extracellular improved insight interdisciplinary approach mouse model mutant mycobacterial novel novel strategies paralogous gene pathogen polypeptide promoter resistant strain response tuberculosis treatment uptake

项目摘要

Project Summary Evolutionarily distant bacterial species respond to zinc starvation by reprogramming their ribosome assembly, in which the constitutive ribosomal proteins with zinc-binding motifs CXXC (C+) are substituted with alternative zinc-free counterparts (C-) through a transcriptional de- repression mechanism involving the zinc uptake regulator, ZurB. The alternative ribosomes assembled with C- ribosomal proteins reduce the zinc requirement for cellular growth under zinc-limiting conditions. Mycobacterium tuberculosis (Mtb), the etiological agent for tuberculosis (TB), has four C+/C- ribosomal protein pairs. All four genes encoding C- proteins of the pair are organized in an operon and are co-expressed through a ZurB-repressible promoter. Co- expression implies simultaneous substitution of all four C+ proteins by C- paralogs, raising questions about the influence of the substitutions on ribosomal response to antibiotics. We have found that the alternative C- ribosomes in both Mtb and Mycobacterium smegmatis not only reduce the zinc requirement for cellular growth, but also confer tolerance to clinically relevant anti-TB ribosomal antibiotics. We further observed that Mtb express more alternative ribosomes during chronic infection than in early acute phase. We thus hypothesize that expression of alternative ribosomes are the primary reasons underlying the inefficacies of the clinically established ribosomal antibiotics against TB. To facilitate improved targeting of mycobacterial ribosomes we propose to: a) elucidate the mechanistic basis of differential responses of constitutive (C+) and alternative (C-) ribosomes to antibiotics (aim 1), b) identify strategies to target alternative (C-) ribosomes (aim 2) and c) determine the role of alternative ribosomes in pathogenesis of Mtb (aim 3). These studies will ultimately lead to new strategies to target both constitutive and alternative ribosomes in mycobacteria, and thus allow effective clearance of mycobacterial infections.

项目总结