Amino acid-derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Abstract

For millennia, humanity has relied on plants for its medicines, and modern pharmacology continues to reexamine and mine plant metabolites for novel compounds and to guide improvements in biological activity, bioavailability, and chemical stability. The critical problem of antibiotic resistance and increasing exposure to viral and parasitic diseases has spurred renewed interest into drug treatments for infectious diseases. In this context, an urgent revival of natural product discovery is globally underway with special attention directed toward the numerous and chemically diverse plant defensive compounds such as phytoalexins and phytoanticipins that combat herbivores, microbial pathogens, or competing plants. Moreover, advancements in "omics," chemistry, and heterologous expression systems have facilitated the purification and characterization of plant metabolites and the identification of possible therapeutic targets. In this review, we describe several important amino acid-derived classes of plant defensive compounds, including antimicrobial peptides (e.g., defensins, thionins, and knottins), alkaloids, nonproteogenic amino acids, and phenylpropanoids as potential drug leads, examining their mechanisms of action, therapeutic targets, and structure-function relationships. Given their potent antibacterial, antifungal, antiparasitic, and antiviral properties, which can be superior to existing drugs, phytoalexins and phytoanticipins are an excellent resource to facilitate the rational design and development of antimicrobial drugs.

Keywords: amino acids; antibiotic resistance; plant defense; plants; secondary metabolites.

Figure 1

Nonprotein amino acids (NPAAs) with anti-infective properties. Mimosine, leucenol or β-[N-(3-hydroxy-4-pyridone)]-aminopropionic acid (antifungal), β-(3-isoxazolin-5-on-2-yl)-alanine or βIA (antifungal), m-Tyrosine (part of antiviral molecules), nicotinic acid (part of bioactive alkaloids), l-canavanine (antibacterial), and azetidine-2-carboxylic acid, l-Aze, or A2C (part of antibacterial and antifungal molecules).

Figure 2

The biosynthetic pathway of the tomato alkaloids based on Akiyama et al. (221). The nitrogen incorporation occurs in the earlier phase of the biosynthesis from cholesterol (222). The genes names in tomato are shown as yellow entries, while the blue entries are the enzyme activities. 3βHSD, 3β-hydroxysteroid dehydrogenase; 3KSI, 3-ketosteroid isomerase; S5αR, steroid 5α-reductase; 3KSR, 3-ketosteroid reductase.

Figure 3

Selected alkaloids, which have been utilized in in vivo studies: lycorine, berberine, cepharanthine, codonopsinine derivatives and voacamine.

Figure 4

The biosynthetic pathway of camalexin via indole-acetaldoxime (top) based on Mucha et al. (261) and that of cruciferous indoles via indole glucosinolate (bottom) based on Klein and Sattely (262). The dashed arrows and the square brackets emphasize proposed unstable intermediates. The common names of plants producing some compounds are shown italicized in parentheses.

Figure 5

Two possible biosynthetic pathways (Routes 1 and 2) of the linear sulfurous compound allicin from the precursors serine and glutathione based on (276). The immediate precursor of alliin is S-allyl cysteine, which may derive from either serine or glutathione. 14C-Labeled serine feeding experiments led to the formation of 14C-labeled S-allyl-cysteine. However, S-allyl-glutathione and S-allyl-γ-glutamyl-cysteine have been detected in other experiments. The source of the allyl group is unknown for both Routes 1 and 2.

Figure 6

The phenylpropanoid pathway, which leads to a variety of plant defensive compounds starting from phenylalanine via the central intermediate p-coumaroyl-CoA highlighting one of the key enzymes, phenylalanine ammonia lyase (PAL) (298).