With bacteria rapidly evolving resistance to our best antibiotics, scientists are searching high and low for new ones. In recent years promising drug candidates have turned up in some unexpected places, like rattlesnake venom, platypus milk and tobacco flowers – and now, already inside the human body. Researchers from MIT and the University of Naples Federico II have found that a potent peptide normally used for digestion has strong antimicrobial effects, and could form the base of new drugs.
Considering the sheer number of bacteria that call your body home – as well as the myriad health problems that can arise from too many bad bugs in your gut microbiome – it makes sense that the human body would have some defence mechanisms in place. Many antimicrobial peptides are known to play that role, and although they're effective in that specific environment, they aren't usually strong enough to use as antibiotic drugs. At least, not without some tweaking.
"These peptides really constitute a great template for engineering," says Cesar de la Fuente-Nunez, one of the senior authors of the new study. "The idea now is to use synthetic biology to modify them further and make them more potent."
To try to identify some of the best candidates, the researchers screened almost 2,000 human proteins, with algorithms designed to flag those with similarities to known antimicrobial peptides. These could then be potential targets for further study.
"It's a data-mining approach to very easily find peptides that were previously unexplored," says de la Fuente-Nunez. "We have patterns that we know are associated with classical antimicrobial peptides, and the search engine goes through the database and finds patterns that look similar to what we know makes up a peptide that kills bacteria."
Of the thousands of peptides screened, the algorithm identified about 800 as potential antimicrobial candidates. For the current study, the researchers singled out one particularly promising peptide, known as pepsinogen, which is involved in digesting proteins in the stomach.
The peptide itself wasn't what caught the team's eye though – it was the small fragments that are produced as a by-product of the digestion process. Until now these fragments had no known function, but the algorithms flagged them as potentially antimicrobial.
To test out how well the pepsinogen fragments worked, the team exposed bacteria populations to them in the lab. Sure enough, the proteins were effective against several common pathogens, including Salmonella, E. coli and Pseudomonas aeruginosa, among others. The fragments were found to be effective both at neutral pH levels as well as in more acidic environments like the stomach.
"The human stomach is attacked by many pathogenic bacteria, so it makes sense that we would have a host defense mechanism to defend ourselves from such attacks," says de la Fuente-Nunez.
Mouse tests also revealed that the fragments are effective at killing skin infections of Pseudomonas aeruginosa.
The next steps for the team are to modify the fragments to make them even more potent, as well as investigating some of the other candidates returned by the algorithm.
The research was published in the journal ACS Synthetic Biology.
Source: MIT
