Targeting host-specific metabolic pathways-opportunities and challenges for anti-infective therapy

Abstract

Microorganisms can takeover critical metabolic pathways in host cells to fuel their replication. This interaction provides an opportunity to target host metabolic pathways, in addition to the pathogen-specific ones, in the development of antimicrobials. Host-directed therapy (HDT) is an emerging strategy of anti-infective therapy, which targets host cell metabolism utilized by facultative and obligate intracellular pathogens for entry, replication, egress or persistence of infected host cells. This review provides an overview of the host lipid metabolism and links it to the challenges in the development of HDTs for viral and bacterial infections, where pathogens are using important for the host lipid enzymes, or producing their own analogous of lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) thus interfering with the human host's lipid metabolism.

Keywords: LCAT; LPL; anti-infectives; drug development; host-directed therapy; intracellular pathogens; lipid enzymes.

FIGURE 1

Exogenous Lipoprotein Pathway (figure modified from “Introduction to Lipids and lipoproteins”. K.R.Feingold, https://www.ncbi.nlm.nih.gov/books/NBK305896/).

FIGURE 2

Endogenous Lipoprotein Pathway (figure modified from “Introduction to Lipids and lipoproteins”, K.R.Feingold, https://www.ncbi.nlm.nih.gov/books/NBK305896/).

FIGURE 3

LCAT in HDL metabolism (figure modified from “Introduction to Lipids and lipoproteins”, K.R.Feingold, https://www.ncbi.nlm.nih.gov/books/NBK305896/).

FIGURE 4

Scaffolds of the small molecules currently identified as LCAT activators.

FIGURE 5

Cartoon of LCAT domains and the various areas of binding of Compound A (1, Figure 4), and DS compounds, e.g., 6, (Figure 4), with Cys31 near the active site and Met49/Tyr51 of the lid, respectively. The active sites of many lipases are contained in the N-terminal domain and controlled by a so-called lid. The catalytic triad, Ser-Asp-His, is at the bottom of lid’s crevice (Berton et al., 2007). The lid domain covers the active site to control both enzyme activation and substrate specificity.

FIGURE 6

Scaffolds of the small molecules currently identified as LPL activators.

FIGURE 7

Bacterial molecular targets in the lipid metabolic pathways of the host (Figure 3) and their effects on lipid metabolism.

FIGURE 8

Structures of drugs affecting the cholesterol levels approved by the FDA for CVD-alternative illnesses; Nevirapine as anti-HIV treatment and Tofacitinib for treatment of rheumatoid arthritis, that have a favorable effect in increasing ApoA-I and reducing cholesterol ester catabolism, respectively.

FIGURE 9

Tetrahydrolipstatin (a representative of statin class of drugs), with the lactone ring as the electrophile responsible for its activity boxed. Lipstatin, a product of Streptomyces toxytricini mold inhibits mammalian lipases. Tetrahydrolipstatin (Orlistat), an FDA approved drug synthesized from lipstatin, binds to lipases in the gastrointestinal tract, thus blocking the digestion of dietary triacylglycerols.