Natural products as inspiration for the development of bacterial antibiofilm agents

Abstract

Natural products have historically been a rich source of diverse chemical matter with numerous biological activities, and have played an important role in drug discovery in many areas including infectious disease. Synthetic and medicinal chemistry have been, and continue to be, important tools to realize the potential of natural products as therapeutics and as chemical probes. The formation of biofilms by bacteria in an infection setting is a significant factor in the recalcitrance of many bacterial infections, conferring increased tolerance to many antibiotics and to the host immune response, and as yet there are no approved therapeutics for combatting biofilm-based bacterial infections. Small molecules that interfere with the ability of bacteria to form and maintain biofilms can overcome antibiotic tolerance conferred by the biofilm phenotype, and have the potential to form combination therapies with conventional antibiotics. Many natural products with anti-biofilm activity have been identified from plants, microbes, and marine life, including: elligic acid glycosides, hamamelitannin, carolacton, skyllamycins, promysalin, phenazines, bromoageliferin, flustramine C, meridianin D, and brominated furanones. Total synthesis and medicinal chemistry programs have facilitated structure confirmation, identification of critical structural motifs, better understanding of mechanistic pathways, and the development of more potent, more accessible, or more pharmacologically favorable derivatives of anti-biofilm natural products.

Figure 1.

Natural products isolated from plants that have demonstrated anti-biofilm activity.

Figure 2.

Second generation hamamelitannin analogues.

Figure 3.

Microbial natural products that have demonstrated anti-biofilm activity.

Figure 4.

Carolacton analogues 71-77.

Figure 5.

Halogenated phenazines and quinolones 101-120.

Figure 6.

Marine natural products that have demonstrated anti-biofilm activity.

Figure 7.

Bromoageliferin inspired compounds with anti-biofilm activity.

Figure 8.

Flustramine inspired compounds with anti-biofilm activity.

Figure 9.

Meridianin D analogues with anti-biofilm activity.

Figure 10.

Brominated furanones with anti-biofilm activity.

Scheme 1.

Synthesis of ellagic acid glycosides 15, 16, and 20.

Scheme 2.

Hamamelitannin 21 and synthesis of first generation hamamelitannin analogues.

Scheme 3.

Total synthesis of carolacton 53.

Scheme 4.

Total synthesis of skyllamycins B 78 and C 79. Top: synthesis of non-proteogenic amino acids. Bottom: Construction of natural products.

Scheme 5.

Synthesis of promysalin 99 and structures of analogues 108-110.

Scheme 6.

Total synthesis of bromoageliferin 128.

Scheme 7.

Synthesis of flustramine C 160 and deformylflustrabromine 161.

Scheme 8.

Synthesis of meridianin D 180.