Natural Antibiotic Synthesis Mechanisms Uncovered

Scientists have discovered a new protein that likely will advance the search for new natural antibiotics. [NIH]

Understanding the molecular mechanisms that trigger the production of antibiotic compounds, especially through the regulation of gene expression, could help scientists advance the search for new natural antimicrobial agents. Now, a group of investigators, led by researchers at Texas A&M AgriLife Research, has discovered a new protein that could prove invaluable as many researchers continue their hunt for new natural products.

The recent findings deal with how proteins regulate gene expression. Scientists have known a great deal about how proteins that control certain gene clusters get their start—referred to as transcription initiation. However, much less is known about transcription elongation where proteins keep gene expression going through “roadblocks” in the DNA sequence.

“The upshot is that our discovery expands the basic knowledge of processive antitermination—a type of genetic regulation—and demonstrates that the mechanism is more widespread among bacteria than previously thought,” explained co-senior study investigator Paul Straight, Ph.D., associate professor in the department of biochemistry and biophysics at Texas A&M AgriLife Research**. “Antibiotic production by bacteria involves complex chemistry that is often encoded in a collection or 'cluster' of many genes. To express these giant gene clusters requires special regulation mechanisms. Understanding these mechanisms could help a great deal in the search for new antibiotics produced by bacteria.”

The findings from this study were published recently in Nature Microbiology in an article entitled “LoaP Is a Broadly Conserved Antiterminator Protein That Regulates Antibiotic Gene Clusters in Bacillus amyloliquefaciens.”

The authors describe two discoveries in their new paper. One is the protein they named LoaP, which stands for long operon-associated protein. The other discovery is that this protein is frequently found next to the gene clusters that are responsible for producing antibiotics. Hence, knowing how LoaP works and its prime location could lead scientists to a shortcut for antibiotic production.

“These long chains of genes raise challenges for the molecular machines that decode DNA,” Dr. Straight noted. “Sometimes the molecular machines hit roadblocks, called terminators, and they stop and fall off the DNA. The LoaP protein is called a processive antiterminator because it helps the machines stay on DNA and move through the roadblock terminators.”

The research team discovered the LoaP protein in Bacillus amyloliquefaciens, a bacterium known to ward off pathogens that attack plant roots in agriculture, aquaculture, and hydroponic production.

“In this study, we analysed the phylogenetic distribution of the large, widespread NusG family of transcription elongation proteins and found that it includes a cohesive outgroup of paralogues (herein coined LoaP), which are often positioned adjacent or within gene clusters for specialized metabolites,” the authors wrote. “We established Bacillus amyloliquefaciens LoaP as a paradigm for this protein subgroup and showed that it regulated the transcriptional readthrough of termination sites located within two different antibiotic biosynthesis operons.”

The researchers noted that while the Earth has an abundant and diverse supply of microbes such as bacteria, many of them with useful biomedical purposes, a modern limitation to antibiotic discovery is the murky understanding of the genetic regulatory mechanisms that oversee their production.

“After nearly a century of searching for bioactive natural products, bacteria still constitute a major target of modern drug discovery,” Dr. Straight said. “The characterization of the biochemical pathways of these molecules remains a bottleneck to their development.”

Dr. Straight concluded that “one of the key restrictions is a shortage of knowledge on the range of genetic mechanisms that can affect them. Therefore, the discovery of new classes of genetic regulatory mechanisms is likely to impact future development of natural products that counter disease.”

** In the current study, Dr. Straight and his graduate assistant Chengxi Zhang of College Station, teamed up with University of Maryland researchers Jonathan R. Goodson, Steven Klupt and Dr. Wade Winkler.