Researchers are developing a covalent bond-inspired “warhead” molecule to hunt down deadly bacteria

Researchers are developing a covalent bond-inspired “warhead” molecule to hunt down bacteria

A team of chemists from Boston College has developed a novel approach to identify and target deadly bacteria using a so-called warhead molecule.

Researchers in medicinal chemistry have long been seeking to develop several approaches to effectively identify and target bacterial pathogens within the human body. In addition, 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.

Nonetheless, the new approach developed by Boston College chemists centres on covalent bonding, especially the covalent chemistry of lipid.

“In contrast to other efforts focused on the charge-to-charge attraction between molecules, we are using a completely different mechanism to target bacterial cells,” said Jianmin Gao, lead author and associate professor of chemistry at Boston College. “Our method exploits the covalent chemistry of lipids—where the lipids react with synthetic molecules to form new chemical structures based on the formation of new covalent bonds.”

Bacterial cells display a different set of lipids in their membranes. Previous researches have explored the use of positively charged peptides to target negatively charged lipids on the surface of bacterial cells. However, this approach has limited success. The presence of salt and other molecules usually weaken the charge-to-charge attraction between the attacking molecules and bacteria.

Gao and his team developed an unnatural amino acid that serves as an appropriate molecular warhead for targeting bacterial pathogens. This amino acid forms a new covalent bond called iminoboronates with bacterial lipids known as amine-presenting lipids, specifically phosphatidylethanolamine and lysyl phosphatidyglycerol.

It is important to highlight the fact that the majority of mammalian cells often lack amine-presenting lipids in their surfaces. Thus, the novel approach has a high degree of selectivity—exclusively targeting bacterial cells. In case of unintended targeting of a few but critical mammalian cells with amine-presenting lipids in their surfaces, the novel approach can harbor a self-correcting feature. After all, the formation of iminoboronates is reversible under certain physiological conditions.

A large number of bacterial species have phosphatidylethanolamine and lysyl phosphatidyglycerol on the surfaces of their cells. The novel covalent-centered approached developed by Gao and his team opens newer possibilities concerning the diagnosis of bacterial infection, as well as the delivery of powerful antibiotic therapy without harming human cells.

“For the short term, we hope this work will inspire other people to consider using covalent chemistry for interrogating biological systems,” said Gao. “Going into the future, we are excited to explore the potential of our chemistry for imaging bacterial infections. We are also working hard to apply our current findings to facilitate the targeted delivery of potent antibiotics to bacterial cells only.”

Further details of the study are found in the article “Targeting bacteria via iminoboronate chemistry of amine-presenting lipids” published in 2015 in the journal Nature Communications.