Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection

Abstract

Despite global efforts to contain tuberculosis (TB), the disease remains a leading cause of morbidity and mortality worldwide, further exacerbated by the increased resistance to antibiotics displayed by the tubercle bacillus Mycobacterium tuberculosis. In order to treat drug-resistant TB, alternative or complementary approaches to standard anti-TB regimens are being explored. An area of active research is represented by host-directed therapies which aim to modulate the host immune response by mitigating inflammation and by promoting the antimicrobial activity of immune cells. Additionally, compounds that reduce the virulence of M. tuberculosis, for instance by targeting the major virulence factor ESX-1, are being given increased attention by the TB research community. This review article summarizes the current state of the art in the development of these emerging therapies against TB.

Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

“…The observed anti-infective phenotype might be caused by accumulation inside Dd, which we speculate is unlikely, since Dd is known to rapidly export xenobiotics through its array of ABC transporters (Anjard et al, 2002; Miranda et al, 2013), as it seems to be the case for rifampicin. An anti-infective phenotype is thus likely to be caused by an antivirulence or host-directed defence booster mode of action (Gries et al, 2020).…”

“…The drug's concentration in lipid droplets of the host cell (Greenwood et al, 2019) might play a substantial role in its mode of action and emphasizes the need of considering host biology when searching for new drugs. Besides unlocking host targets, host-pathogen screening systems also have the potential to guide the way to targets within bacterial effectors, which are specific for the intracellular life of mycobacteria (Gries et al, 2020). Compounds with such an activity have been identified by investigating hits from a host-pathogen screen, which were inactive in a screen on mycobacteria (Rybniker et al, 2014).…”

Editorial on Special Issue “Tuberculosis Drug Discovery and Development 2019”

“…The Special Issue then features a series of articles dedicated to the most relevant and frequently explored drug targets: the cell wall of M. tuberculosis is reviewed by Vilchèze [11], DprE1 and MmpL3 are described by Degiacomi and co-workers [12], and the oxidative phosphorylation pathways are presented by Foo and colleagues [13]. In addition, Gries et al report on the most recent advances in host-directed therapies and anti-virulence compounds, which could represent a helpful complement to current anti-TB approaches [14]. In the context of additional approaches to standard antibiotic treatment, an article by Visca et al reviews the importance of post-TB treatment with the roles of surgery and rehabilitation [15].…”

Design of a specific peptide against phenolic glycolipid-1 from Mycobacterium leprae and its implications in leprosy bacilli entry

“…(4) In mycobacteria, this approach has been explored only in Mycobacterium tuberculosis and Mycobacterium marinum, and the approach targeted the PhoPR regulon, SapM, and ESX-1 secretion system. (4,5,6) Some promising candidates are in the preclinical stages and are being tested in animal models. Hansen's disease is characterised by loss of sensitivity at the peripheral nerve level due to irreversible tissue damage and subsequent weakening by the infection chronicity.…”

“… 4 In mycobacteria, this approach has been explored only in Mycobacterium tuberculosis and Mycobacterium marinum , and the approach targeted the PhoPR regulon, SapM, and ESX-1 secretion system. 4 , 5 , 6 Some promising candidates are in the preclinical stages and are being tested in animal models.…”