Host-directed therapies for bacterial and viral infections

Abstract

Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with soluble factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory molecules). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

“…NAD + replenishment could be combined with reagents that promote mitochondrial function, such as RSV and CsA, which were previously shown to protect macrophages from Mtb-induced cell death (Cheng et al, 2017; Gan et al, 2005). These host-targeted strategies could be combined with antibacterial drugs to improve TB chemotherapy (Kaufmann et al, 2018; Nathan and Barry, 2015). These implications may also apply to other bacterial and fungal pathogens that utilize NAD + glycohydrolases, such as S. pyogenes (Chandrasekaran and Caparon, 2015) and the over 300 microorganisms encoding TNT homologs (Danilchanka et al, 2014).…”

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

“…Host-directed therapies [126], microbiome alterations (e.g. probiotics) [127], nanotechnology [128], endolysins [129], and bacteriocins [130] have all been investigated as novel treatments for bacterial infections.…”

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity

“…Alternatively, strategies that inhibit host cellular factors critical for viral infection rather than viral proteins have the potential to be more broad spectrum, more refractory to developing drug resistant mutants and provide a different mode of action that complements direct-antiviral drugs (Kaufmann et al, 2017). Recent genome-wide genetic screens revealed several endoplasmic reticulum (ER)-localized protein complexes to be essential for viral infection (Ma et al, 2015; Marceau et al, 2016; Savidis et al, 2016; Zhang et al, 2016).…”