Abstract
Tuberculosis (TB) caused by the intracellular pathogen Mycobacterium tuberculosis (MTB) continues to threaten public health globally. Considering the wide emergence of drug resistant MTB strains, particularly Multi-Drug Resistant (MDR-) and extensive Drug-Resistant (XDR-) TB, achieving the STOP-TB goal by 2050 remains questionable and challenging. One of the principal components in eradicating and eliminating TB and guaranteeing global TB control is the development of new treatment and prevention tools, including drugs and vaccines. The first and crucial step of this process is the identification of targets within the bacterial pathogen, which is driven by understanding the complex interplay between pathogen and host, as these interactions are key factors in determining the outcome of the MTB infection. We generated MTB and host (human) intra-species and the host-pathogen inter-species functional interaction networks using genomic and functional data retrieved from high-throughput experiments. In previous work, the MTB functional network was used to identify 881 proteins potential drug targets within this organism which provided the opportunity to expand the range of existing drug targets. Here we are using the functional interplay between host and pathogen to filter and prioritize the set of targets. This yields a filtered set of targets which also consider the host system and effects on host-pathogen interactions by leaving out proteins predicted to interact with human proteins. Further functional and statistical analyses were conducted in which uncharacterized proteins and those with paralogs were removed, resulting in a reduced list of protein targets with essential functions and no functional connections with human proteins.
Highlights
Despite the wide variety of anti-tuberculosis drugs, tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a public health challenge today, claiming millions of lives and new cases every year
MTB intra-species functional networks and a human-MTB inter-species functional network to filter a list of 881 protein targets previously identified within MT B using topological properties of its protein-protein functional interaction network [10]
Since an efficient drug target should prevent growth of the pathogen, we identified which of our targets were essential for growth. 79 and 21 out of 400 annotated protein targets were found in the two lists of genes, which were experimentally identified by Sassetti et al [35,36] to be required for normal MTB growth and for its survival during infection, respectively
Summary
Despite the wide variety of anti-tuberculosis drugs, tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a public health challenge today, claiming millions of lives and new cases every year This success of MTB is in part due to the discontinuity of its life cycle in the host system, owing to its ability to enter and exit from different states in response to the antimycobacterial host defense mechanisms, enabling it to infect, grow, persist and survive in human macrophages [1]. Enhanced service provision of the existing antibiotics in recent years through Direct Observed Treatment (DOT) as implemented by the World Health Organization (WHO) is of immense value in controlling the disease These drugs have several shortcomings, the most important being the emergence of drug resistance, making even the front-line drugs ineffective. As current anti-tuberculosis drugs are not sufficiently efficient, prone to development of multi-drug resistance and no new anti-tuberculosis drugs have been designed for over 20 years, it is increasingly important to pursue new and effective strategies to confront the challenge of TB in this 21st century
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