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New Antibiotics Discovered in Stomach Peptides

Pseudomonas aeruginosa

Pseudomonas aeruginosa colony (Harvard Medical School, NIH)

21 August 2018. Researchers in Italy and the U.S. found a potential source of new antibiotics in derivatives of peptides used by the digestive process in the stomach. A team from Massachusetts Institute of Technology and University of Naples Federico II report their findings in yesterday’s issue of the journal ACS Synthetic Biology (paid subscription required).

The emergence of bacteria that resist today’s antibiotics is a continuing and growing problem. The wide use of antibiotics — in some cases over-use of these drugs — contributes to microbes evolving into strains that can evade current antibiotics, making infections more difficult to treat. Centers for Disease Control and Prevention says in the U.S., some 2 million people a year develop infections from microbes resistant to antibiotics, leading to 23,000 deaths.

Researchers led by MIT bioengineering postdoctoral fellow César de la Fuente-Nunez and Naples biochemistry professor Eugenio Notomista are seeking new sources for antibiotics to meet this challenge. Their search began with peptides generated naturally by the digestive system to protect against infections. Peptides are short chains of amino acids that resemble proteins, and can break through the cellular membranes of bacteria to damage their DNA and protein-producing functions. But by themselves peptides lack the power to treat infections, which calls for developing synthetic peptides that retain their chemical activity but function more like medications.

In earlier research, de la Fuente-Nunez and colleagues developed an algorithm for screening databases of human proteins for chemical properties similar to peptides. In this study, the team refined the algorithm to discover human proteins, with chemistries more complex than peptides, and screened some 2,000 proteins for antimicrobial characteristics like those in peptides. Their screening initially returned 800 proteins, but one protein known as pepsin A showed particular promise. Pepsin A is a protease, a type of digestive enzyme that breaks down the peptide pepsinogen. Residual fragments of pepsinogen, previously unknown to the team, were shown in further screening to have distinct antimicrobial properties against foodborne bacteria such as E. coli.

“The human stomach is attacked by many pathogenic bacteria,” says de la Fuente-Nunez in an MIT statement, “so it makes sense that we would have a host defense mechanism to defend ourselves from such attacks.”

The researchers produced synthetic forms of three pepsinogen fragments and found in lab cultures they have antimicrobial properties, killing E. coli and Salmonella, another foodborne bacteria. The team then tested the synthetic peptide fragments with lab mice, induced with skin infections from Pseudomonas aeruginosa, a bacterium responsible for pneumonia is health care settings, as well as blood stream infections. The researchers say the synthetic peptides reduced the bacterial load in the mice infections by up to 4 orders of magnitude.

The team plans to refine the synthetic peptides tested in this study into antibiotic candidates, but they also want to extend the technology to other human peptides identified in their screening. De la Fuente-Nunez notes the researchers already collected a library of these peptides, “and the next step is to demonstrate whether each of them actually has antimicrobial properties and whether each of them could be developed as a new antimicrobial.”

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