Bacteria-killing viruses known as bacteriophages often produce enzymes that can degrade the bacterial cell wall, and whose structure can be used to identify enzymes with similar properties in other microorganisms. Image credit: Servier Medical Art (CCBY 4.0)
Bacteria are increasingly becoming resistant to antibiotics, leading to a rise in cases of dangerous diseases around the world. Innovative treatments are urgently needed, prompting researchers to turn to alternative approaches.
One strategy is to focus on finding new ways to target the bacterial cell wall, a shield-like structure that wraps around the cell and protects it against the environment. Certain hydrolase enzymes can weaken this wall by breaking down its primary component, a type of molecules known as peptidoglycans. Lysins, for example, are produced by phage viruses (which prey on bacteria) and have gathered momentum as antimicrobial agents.
However, clinical studies so far have largely focused on using peptidoglycan hydrolases against Gram-positive bacteria, in which peptidoglycans are directly exposed to the environment. In Gram-negative species, on the other hand, the cell wall includes an outer membrane that makes it harder for the enzymes to access their targets. Finding better phage-derived lysins that work against Gram-negative bacteria has been challenging so far, partly because this would require scanning the genomes of various phage species for candidates – an information that is difficult to access.
Instead, Zhang et al. turned to peptidoglycan hydrolases produced by bacteria themselves, for example to eliminate competitors. To find these enzymes, the team used a specific structure in a phage-derived lysin as a template; known as P307, this short sequence (or peptide) allows the viral enzyme to cross the outer membrane of Gram-negative bacteria and reach the peptidoglycans below.
Using a range of computational method, P307 was screened against the pool of proteins produced by the bacterium Acinetobacter baumannii. This revealed five bacterial peptidoglycan hydrolases, two of which had the potent ability to kill harmful species of Gram-positive and Gram-negative bacteria both in vitro and in mice. They retained this ability even after having been exposed to high temperatures, with further experiments pointing to unique structural properties underlying this stability. Taken together, these findings highlight an effective method to identify new bacterial-derived peptidoglycan hydrolases that could serve as antimicrobial agents.
