Phazolicin or PHZ, the newly discovered ribosome-disrupting compound. Why this is a big deal

According to Harvard University, only 15 new antibiotics have been approved since 2000, compared to over 60 between the years of 1980 and 2000. (see chart below). Out of these 15 new drugs, only 4 of them represent new classes of antibiotics (that is targeting bacteria through novel mechanisms).

But there are new strategies in the pipeline, including an antibiotic “designed for plants” that also could be beneficial to humans., though not in the way you might think.

 

PHZ is a new linear azol(in)e-containing peptide found in root nodules of wild beans (Phaseolus vulgaris, growing in the tropical forest in Los Tuxtlas, Mexico), and is produced by a new symbiotic soil bacterium Rhizobium. PHZ, can be used as a ‘plant probiotic’, preventing other harmful bacteria from growing. 

Antibiotics were first introduced to human medicine in the 1950s as ‘miracle drugs,’ and were quickly investigated for curing plant diseases. The typical definition of an antibiotic is a “substance produced by one microorganism that inhibits or kills other microorganisms.” The first studies in plants looked at 40 antibiotics that could work for plant disease control. To be viable the drugs had to meet certain criteria:

  • Be active on or inside the plant,
  • Tolerate a number of conditions (oxidation, UV irradiation, rainfall, high temperatures, etc.)
  • Be safe for plants,
  • Be selective (targeting vulnerable targets specific to plants that preferably do not exist in animals)

The first global antibiotic: Triumphs and challenges

Only a single compound (streptomycin) made the cut and has been used worldwide since then. Similar to the antibiotic resistance seen in human medicine, streptomycin eventually caused a huge destabilisation in plant disease control. Antibiotic resistance has become a problem in pathosystems where bacteria have evolved through the horizontal gene transfer or mutation to survive compounds that have been used for many years. Luckily only a very small fraction of plant diseases caused by bacteria are currently managed by antibiotics. But that small fraction represents staple crops that require a lot of human input to ensure their proper growth and suitable yield.

Legume crops (like beans, nuts, peas and lentils), for example, struggle with Agrobacterium strains (tumour-causing bacteria) or rhizobium inoculants (nitrogen exchange system). Some legumes can’t absorb nitrogen like other plants do, instead forming symbiotic relationships with rhizobia, and working together to take nitrogen gas from the atmosphere to convert into a plant form. Rhizobia form root nodules on the host legume, providing the plant with transformed nitrogen in exchange for a portion of the sugars made by the plant.discovery.

The power of genomics

Discovering phazolicin was made possible due to the constantly growing and ever-increasing genomic data, making the strategies based on genome mining considerably easier. Traditional screening methods (activity-based assays), usually lead to rediscovery of the already known compounds. By using bioinformatics from the latest genomic sequencing methods, researchers found the new peptide within the genome of a wild bean bacterium – leading up to the discovery of the new molecule.

The newly discovered compound attacks a diverse group of bacterial cells and binds to bacterial ribosomes, disrupting their ability to synthesise proteins. The discovery is particularly fascinating, as PHZ represents the second linear thiazole/oxazole-modified peptideever to be characterised. The peptide targets the bacterial ribosome.

The mode of action of phazolicin was determined in vivo and in vitro using E.coli based systems, allowing for identification of antibiotics inducing ribosome stalling or inhibiting DNA replication. The study found that phazolicin inhibits the elongation step of prokaryotic translation by obstructing the NPET of the large ribosomal subunit. The new probiotic cold be used for more than just biocontrol in agriculture, leading to new antibiotics in clinical medicine. By introducing small mutations in ribosomes, scientists from Rutgers University, discovered they can modify and control bacteria’s susceptibility to the antibiotic.

To summarize, newly discovered phazolicin prevents harmful bacteria from entering the root system of legumes by inhibiting their protein production and binding to ribosomes. Senior author Konstantin Severinov, a principal investigator at the Waksman Institute of Microbiology based at Rutgers, said in a statement “we hope to show the bacterium can be used as a ‘plant probiotic’ because phazolicin will prevent other, potentially harmful bacteria from growing in the root system of agriculturally important plants,” in turn helping to grow food more sustainably and with increased yield.

Additionally, the discovery of phazolicin can be used in aiding the fight against one of the biggest challenges of human history – antibiotic resistance. The method of action and ribosomal targeting could be used in the development of new medicines for clinical use. Due to the overuse and misuse of drugs and natural evolution, several strains of bacteria developed immunity to some of the currently used antibiotics, in turn making them less effective.

The new discovery brings hope that new antibiotics can still be found, and with the ever-increasing knowledge and skills of our scientists, brought to market before we run out of time.