What are Microbiome-Derived Antibiotics?

By Ahmed Donia, Ph.D.Reviewed by Emily Henderson, B.Sc.

Identification of different antimicrobials of human microbiota origin is one of the most promising solutions to combat the growing problem of antibiotic resistance. Current researches focused on finding novel antimicrobials from the gastrointestinal tract. This may be due to the considerable number of antimicrobial producers and the vast array of inhabitant microbes in the gastrointestinal tract.

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Gut microbiota distribution and composition

The composition of gut microbiota is heterogeneous across the gastrointestinal tract due to differences in a broad variety of parameters such as fluctuations in pH, gas composition temperature, and water activity as well as variations in physiology throughout the gut. It is important to consider that the gut microbiota composition is not static and shifts over time. The microbiota carries out a variety of molecular and metabolic functions.

Bacteroidetes, Proteobacteria, Actinobacteria, Firmicutes, and Verrucomicrobia are the dominant bacterial phyla in the gut. Variation in physiological conditions leads to a heterogeneous distribution of bacteria across the gastrointestinal tract. The highest microbial density is in the colon due to slow transit time and a lack of easily digestible nutrients. This leads to the proliferation of fermentative organisms which can degrade more complex compounds, such as dietary fiber.

Although bacteria have been most extensively studied, there are other microbial groups in the human gastrointestinal tract that have not been well researched but play a pivotal role in the ecological dynamics, like eukaryotes, viruses, and archaea.

Bacteria, viruses, eukaryotes, and archaea coexist in the human gastrointestinal tract, and this microbiota coexistence is functionally balanced by antagonistic or symbiotic relationships. The production of antimicrobials against other organisms occupying the same environmental niche is a typical example antagonistic relationship. The development of specialized antimicrobials, which is the result of close co-evolution in the gut, may serve as novel alternatives to antibiotics.

Microbiome-derived antimicrobial activity

Bacteria can develop various antagonism strategies to gain ecological advantages over other bacteria occupying the same environmental niche in the gastrointestinal tract. Lowering the oxidation-reduction potential, accumulation of D-amino acids, competitive removal of essential substrates, and co-aggregation are examples of direct strategies.

The production of substances of metabolic origin such as hydrogen peroxide, which can restrict the growth of surrounding bacteria, is an example of another strategy. Hydrogen peroxide, which has an antimicrobial effect, could contribute to maintaining a healthy microbiota. It synergistically functions with other materials secreted by bacteria, such as lactic acid, which is produced by the metabolism of carbohydrates of lactic acid bacteria.

The undissociated forms of lactic acid and other organic acids cross the lipid membrane and then dissociate in the neutral pH once inside cells, producing ions that result in stress inside cells. Bacteria fermenting proteins, starches, sugars, dietary fiber, and amino acids produce short-chain fatty acids, which perform their antimicrobial activity via acidification of the environment. There are other compounds of bacterial origin such as ammonia or phenolic compounds, diacetyl (2,3-butadione), ethanol, CO2, which are well known for their antimicrobial properties.

Bacteria can also produce antimicrobial peptide compounds, which have target-specificity features. There are two main types of peptides with antimicrobial properties that are classified based on their biosynthesis: ribosomal or non-ribosomal peptides. Antimicrobial peptides generally consist of ten to fifty amino acids and their ability to kill bacteria is based on their interaction with cell walls and bacterial membranes. Their selectivity depends on the composition of the membrane or cell wall.

Production and accumulation levels of these peptides in the gastrointestinal tract depend on bacteria producing-strains, their bioavailability, physical conditions within the surrounding environment, and chemical structure, making the identification and direct isolation of those peptides a hard mission.

Many important bacteriocins, which are ribosomally synthesized peptides with antimicrobial activity, are produced by bacteria that inhabit the gastrointestinal tract of humans. Given the diversity and density of microbial populations present in the gastrointestinal tract, it is considered to be a source of bacteriocin producer.

Bacteriocins have low toxicity, making them suitable as preservatives for beverage and food products since traditional antibiotics cannot be used in food. Some bacteriocins can exhibit broad-spectrum, which could be used as traditional therapeutic antibiotics. Bacteriocins with narrow-spectrum are more preferred for targeting specific harmful microorganisms without altering the natural populations, making them ideal to maintain a balance in microbial populations.

There is a low possibility to develop resistance against bacteriocins. In general, bacteriocins produced by Gram-negative bacteria show better activity against Gram-negative pathogens, and Gram-positive bacteriocins work well on Gram-positive pathogens.

Further Reading

• All Drug Discovery and Manufacturing Content
• Drug Discovery, Manufacturing, and Development
• What are Peptide Decoys?
• Using Artificial Intelligence to Discover New Antibiotics
• Applications of 3D printing in Drug Delivery