Abstract
Tuberculosis is a leading infectious disease causing millions of deaths each year. How to eradicate mycobacterial persistence has become a central research focus for developing next-generation TB drugs. Yet, the knowledge in this area is fundamentally limited and only a few drugs, notably capreomycin and PA-824, have been shown to be active against non-replicating persistent TB bacilli. In this study, we performed a new bioinformatics analysis on microarray-based gene expression data obtained from the public domain to explore genes that were differentially induced by drugs between the group of capreomycin and PA-824 and the group of mainly the first-line TB drugs. Our study has identified 42 genes specifically induced by capreomycin and PA-824. Many of these genes are related to stress responses. In terms of the distribution of identified genes in a specific category relative to the whole genome, only the categories of PE/PPE and conserved hypotheticals have statistical significance. Six among the 42 genes identified in this study are on the list of the top 100 persistence targets selected by the TB Structural Genomics Consortium. Further biological elucidation of their roles in mycobacterial persistence is warranted.
Highlights
Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis that typically affects the lungs but may occur in other organs, such as the central nervous system, lymphatic system, circulatory system, genitourinary system, bones, joints, and the skin
The four gene-expression data samples concerning the responses of M. tuberculosis to capreomycin and PA-824 at a low and high doses constituted the experimental group, and the rest of data samples representing the responses of M. tuberculosis to other selected drugs is assigned to the control group
Positive significant genes are genes that are differentially expressed in response to capreomycin and PA-824
Summary
Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis that typically affects the lungs (pulmonary TB) but may occur in other organs (extrapulmonary TB), such as the central nervous system, lymphatic system, circulatory system, genitourinary system, bones, joints, and the skin. Persistent bacilli refer to those nongrowing bacilli that, often derived from in vivo, can grow immediately in a fresh medium [1]. Dormant bacilli refer to nongrowing bacilli that do not grow immediately in a fresh medium but can be resuscitated [1]. Latent TB infection (LTBI) is a clinical condition associated with only a positive tuberculin skin test (i.e., evidence of infection with M. tuberculosis) but without clinical or radiographic signs of active disease. Persons with LTBI are at increased risk for development of active disease, which may occur after decades of latent infection [4]. The distinction between persistent and dormant bacilli seems to be their rates of recovery from the nongrowing state. We do not make distinction between “nonreplicating persistence”
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