A Warhead Molecule To Hunt Down Deadly Bacteria

Targeting deadly, drug-resistant bacteria poses a serious challenge to researchers looking for antibiotics that can kill pathogens without causing collateral damage in human cells. Researchers detail a new approach using a "warhead" molecule to attack bacteria - and spare healthy human cells - by targeting a pair of lipids found on the surface of deadly germs, according to a report in the journal Nature Communications.

The new strategy required the researchers to develop a novel type of "warhead molecule" capable of selectively targeting bacteria, overcoming biological conditions that interfere with bonding to pathogens and avoiding healthy human cells.
 
Pathogenic bacteria that are resistant to conventional antibiotics pose increasingly serious threats to public health. Researchers in medicinal chemistry, particularly those who seek to develop new antibiotics, are constantly looking for new ways to identify and differentiate bacterial pathogens from host cells within the human body.
 
Bacterial cells are known to display a different set of lipids in their membranes. Prior research has focused on the use of positively charged peptides to target negatively charged lipids on the surface of bacterial cells. The approach has seen limited success as the charge-charge attraction between the attacking molecules and bacteria is prone to weakening by the presence of salt and other molecules.
 
The researchers developed a novel, unnatural amino acid that serves as a suitable molecular warhead to target bacterial pathogens. The researchers sent the warhead molecule after bacterial lipids known as amine-presenting lipids - specifically phosphatidylethanolamine (PE) and lysyl phosphatidylglycerol (Lys-PG) - which can be selectively derivatized to form iminoboronates, a covalent bond forming process that allows the selective recognition and labeling of bacterial cells.
 
In addition, because amine-presenting lipids are scarce on the surface of mammalian cells, they are able to seek out and label bacterial cells with a high degree of selectivity. Furthermore, iminoboronate formation can be reversed under physiologic conditions, giving the new method a high degree of control and allowing the warhead molecules to self-correct if unintended targets are reached.
 
A large number of bacterial species present PE and Lys-PG on their surfaces, making the covalent labeling strategy applicable to many applications in the diagnosis of bacterial infections and the delivery of antibiotic therapies.
 
The researchers are currently working on applying the current findings to facilitate the targeted delivery of potent antibiotics to bacterial cells only.
 
Based on materials originally posted by Boston College.