Targeted Antimicrobial Agents as Potential Tools for Modulating the Gut Microbiome

Abstract

The gut microbiome plays a pivotal role in maintaining the health of the hosts; however, there is accumulating evidence that certain bacteria in the host, termed pathobionts, play roles in the progression of diseases. Although antibiotics can be used to eradicate unwanted bacteria, the side effects of antibiotic treatment lead to a great need for more targeted antimicrobial agents as tools to modulate the microbiome more precisely. Herein, we reviewed narrow-spectrum antibiotics naturally made by plants and microorganisms, followed by more targeted antibiotic agents including synthetic peptides, phage, and targeted drug delivery systems, from the perspective of using them as potential tools for modulating the gut microbiome for favorable effects on the health of the host. Given the emerging discoveries on pathobionts and the increasing knowledge on targeted antimicrobial agents reviewed in this article, we anticipate targeted antimicrobial agents will emerge as a new generation of a drug to treat microbiome-involved diseases.

Keywords: antimicrobial peptides; bacteriocins; berberine; microbiome editing; pathobionts; phage therapy; polyphenols; targeted drug delivery system.

Figure 1

Gut pathobionts and their related diseases. CRC: colorectal cancer; CD: Crohn’s disease; UC: ulcerative colitis.

Figure 2

STAMPs can be divided into three categories. (A) Canonical STAMPs are usually discovered by screening a batch of peptides with various parameters including hydrophobicity, cationic number, and secondary structure. These parameters, as well as some bacterial factors, determine the affinity between the peptides and bacterial surfaces. Canonical STAMPs kill bacteria by insertion into the cell membrane, followed by self-oligomerization, pore formation, and cell membrane perturbation. (B) Peptide ligands as STAMPs. This category of STAMPs kills specific bacteria by competitively binding bacterial receptors of physiological importance against the natural ligands of the receptors, resulting in inhibition of important bacterial pathways and subsequential inhibition of bacterial growth. (C) Composite STAMPs consist of a targeted domain and a killing domain. The targeted domain binds to specific motifs on targeted bacteria, which directs the killing domain to kill bacteria in the same way as canonical STAMPs.