Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Abstract

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery.

Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics

“…Identifying specific markers peculiar to patients with latent TB would be beneficial to tackling this challenge. The use of bioinformatics, and the other ‘omics' disciplines, have proved able to identify several potential targets for the survival of Mtb in the latently infected host ( 163 – 165 ).…”

The Biological and Clinical Aspects of a Latent Tuberculosis Infection

“…Granulomas play an important role in arresting the growth and proliferation of Mtb cells. Inside granulomas, they are faced with hypoxia, a lack of nutrients, and high concentrations of nitric oxide [ 50 ]. However, they can survive in these conditions due to their transition to the dormant state and persisting even during the anti-TB chemotherapy [ 3 , 50 , 51 , 52 ].…”

“…Inside granulomas, they are faced with hypoxia, a lack of nutrients, and high concentrations of nitric oxide [ 50 ]. However, they can survive in these conditions due to their transition to the dormant state and persisting even during the anti-TB chemotherapy [ 3 , 50 , 51 , 52 ]. Stress conditions in granulomas lead to the metabolic heterogeneity of Mtb [ 44 , 53 ].…”

“…Currently, various approaches are used for chemoprophylaxis around the world. The use of first-line anti-TB drugs, rifamycin/rifapentine or isoniazid, is widespread [ 50 , 109 ]. This approach to TB chemoprophylaxis appeared in the 1950s and was based on the observation that the treatment of children with isoniazid prevents the development of TB symptoms.…”

“…They are targeted at blocking the enzymes that remain active during the dormant state of Mtb cells: alanine dehydrogenase, isocitrate lyase, cysteine synthase CysM, adenosine-5′-phosphosulfate reductase, DevS and DosT oxygen sensors involved in dormancy response, lysine ε-aminotransferase, enoyl-acyl carrier protein reductase (InhA), decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1), mycocyclosin synthase (Cyp121), and extracellular zinc metalloprotease 1 (Zmp1). Details of the above-mentioned compounds targeting nonreplicating Mtb cells, a description of their chemical structures, and the possible modes of action are provided in the review by Campaniço et al “Addressing latent TB: new advances in mimicking the disease, discovering key targets, and designing hit compounds” [ 50 ].…”