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Building off of nature’s basics
TROY, N.Y.—In hopes of turning bacterial strains’ own mechanisms back on them, a team from the Rensselaer Polytechnic Institute has found a way to attack bacteria through natural weaknesses that bacteria cannot become resistant to. Their work was published in Biomacromolecules, and was led by Jonathan Dordick, a chaired professor of chemical and biological engineering and a member of the Center for Biotechnology and Interdisciplinary Studies (CBIS); postdoctoral researcher Domyoung Kim; and senior research scientist Seok-Joon Kwon.
The Rensselaer team worked in collaboration with a group led by Jungbae Kim, a professor of chemical and biological engineering from Korea University. This research was supported by a grant from the Global Research Laboratory Program through the National Research Foundation of Korea.
The key to this new approach lies in bacterial enzymes, specifically three kinds of cell lytic enzymes: autolysin enzymes, bacteriocin and phage endolysin enzymes. These enzymes consist of a binding domain, which attaches to the cell wall, and a catalytic domain that bores through the cell wall to destroy a targeted cell.
Autolysin enzymes are naturally produced by bacteria to break down their own cell walls to enable division and replication. Bacteriocin is an antibacterial protein produced by bacteria to kill other strains. As for phage endolysin enzymes, those are produced by bacteriophages (viruses that infect bacteria), and they attack a bacterial cell from the inside.
“It’s very difficult for bacteria to become resistant to the action of these enzymes,” Dordick noted. “For example, if they became resistant to an autolysin, they wouldn’t divide.”
He adds that “there is no human equivalent” to autolysin enzymes, which eliminates concerns of off-target damage to healthy human cells.
The enzymes are very specific and target only one or a handful of bacteria, according to Dordick. To explore whether or not they could create their own enzymes, the team started with the protein streptavidin as their template to attach different combinations of binding and catalytic domains.
Dordick tells DDNews that “Our goal was to design completely new enzymes based on the interesting feature of these enzymes where they have two distinct segments—one that binds to the cell wall and one that cuts the cell wall. By separating these segments, we could then treat each like a building block or Lego piece. We could then combine one binding segment with one catalytic segment (or two binding segments with one catalytic segment) at will, and we could do this in many combinations. This resulted in unique enzymes with activity even better than what Nature gave to us.”
Their manmade enzymes proved as effective or more effective as natural combinations when it comes to targeting Staphylococcus aureus, the culprit of the common staph infection.
An added bonus of this approach, beyond being something bacteria cannot develop resistance to, is the sheer speed of the process. “Adding any one of these types of enzymes to its target bacterium results in a dose-dependent cell wall breakdown,” Dordick says. “Even at low concentrations of an enzyme, the cell walls break down in seconds to kill the bacterium. With sufficient enzyme levels (and the amount is quite low), the bacterium dies well before it can repair its cell wall.”
This study was done on Gram-positive bacteria, but Dordick states that their approach should work equally well on Gram-negative bacteria such as Listeria, Streptococcus and Bacillus, bacteria that cause food poisoning, dental plaque and anthrax, respectively. Not all Gram-negative bacteria will be as easy to target, however.
“The more challenging bacteria for our approach are the Gram-negative bacteria, such as E. coli, Salmonella, etc.,” he comments. “These bacteria have an outer membrane that blocks access of our enzyme system to the cell wall. We are now developing additional hybrid enzyme systems that can be used to penetrate the outer membrane and allow access to the cell wall to kill the bacteria. We are also looking at other hybrid systems where direct access to the cell wall may not be necessary, yet could be used to kill bacteria on contact and specific to the pathogens we want to eliminate.”
Beyond tackling the issue of tougher Gram-negative bacteria, Dordick reports that the team is also interested in further exploring this “Lego block” approach by taking it into the microbiome.
“We are interested in designing hybrid enzymes that can target specific pathogens that cause our gut and skin microbiomes to become unhealthy,” he explains. “Thus, we believe we can use our approach to “remodel” microbiomes and make them healthy. We also want to apply our enzyme systems to the environment and eliminate bacteria that pose threats to public places, including hospitals, schools, airports/airplanes, etc.”
“This research has the potential to improve human health,” said Deepak Vashishth, director of CBIS. “It is emblematic of the innovative solutions that are needed to advance medical care.”