Models for the directed evolution of bacterial allelopathy: bacteriophage lysins

Area of Science:

• Microbiology
• Synthetic Biology
• Evolutionary Biology

Background:

• Microbes naturally produce compounds to inhibit other species, forming the basis for traditional antibiotics.
• The search for novel antibacterial drugs relies heavily on discovering and engineering these natural products.
• Allelopathy, the production of toxins by one species to harm another, offers a pathway for directed evolution of antimicrobial compounds.

Purpose of the Study:

• To develop mathematical and computational models for directed evolution of microbial toxins.
• To evaluate the feasibility of using directed evolution to enhance toxin efficacy for antibacterial drug discovery.
• To compare two potential systems for toxin-directed evolution: plasmid-based and phage-based.

Main Methods:

• Mathematical and computational modeling of directed evolution processes.
• Simulation of co-culture systems involving a toxin-producing host and a toxin-susceptible target species.
• Analysis of toxin encoding on plasmids versus bacteriophages.

Main Results:

• The plasmid-based system for directed evolution of toxins shows greater promise than the phage-based system.
• Successful directed evolution requires co-culturing a toxin-resistant host with a susceptible target species, where the host is typically outcompeted unless the target is eliminated.
• The models indicate feasibility for directed evolution in the plasmid system if specific co-culture conditions are met.

Conclusions:

• Directed evolution is a feasible strategy for enhancing microbial toxins, particularly using a plasmid-based system.
• The development of effective co-culture conditions is critical for the success of this directed evolution approach.
• Plasmid-based screening holds potential for the rapid improvement of toxin potency in the pursuit of new antibacterial agents.