The world is rapidly running out of effective antibiotics. For decades, we have relied on a simple course of antibiotics to treat common bacterial infections. However, bacteria are evolving fast to resist our traditional antibiotics and are thereby reducing their effectiveness. In addition, fewer new drugs are moving from the laboratory to clinical trials. In fact, of the fifty-one antibiotics presently in clinical stages of development, only ten are expected to move on to the market in the following five years. Due to low success rates and lack of any specific cellular targets for antibiotics, combined with higher costs in research and development, many pharmaceutical companies are reluctant to invest in developing new antibiotics. Further, there is a high probability of bacteria developing antibiotic resistance to the drugs before or shortly after their arrival in the marketplace.
Without adequate innovations in antibiotic research and development, the diseases currently addressed with an antibiotic course may soon become untreatable. These diseases can cause serious health concerns—including death. Antibiotic resistance is a global health emergency that could hamper progress in modern medicine. Therefore, finding new antibiotic candidates is a crucial area of study for researchers in the world.
The human body: A source of new antibiotic candidates
In recent years, scientists have investigated surprising sources for antibiotics, including Komodo dragons, leaf-cutter ants, rattlesnake venom, platypus milk, and tobacco flowers, and it turns out that the human body itself is a rich source for antibiotics, as well. Scientists at MIT and the University of Naples Federico II have discovered a potent peptide in the human body with antimicrobial properties, paving the way for new antibiotics.
Antimicrobial peptides (AMPs) found in all living organisms act as a first line of defense against bacteria, fungi, parasites, and viruses. They are essential components of the body’s innate immune system. These are generated when larger proteins, including those with no role in host defense, are broken down into smaller peptides.
However, due to their tendency to degrade quickly, AMPs cannot be used as antibiotic drugs without some modification.
In the quest to find novel antibiotic candidates, the researchers developed a search algorithm that picks the patterns in human proteins that are similar to the patterns found in classical antimicrobial peptides. With this approach, scientists could find previously unexplored peptide candidates.The researchers screened nearly two thousand human proteins for similarity to known antimicrobial peptides. The algorithm identified about eight hundred different peptides for antimicrobial activity, and pepsinogen-derived peptides showed remarkable promise. Further screening demonstrated their efficacy against bacterial populations in the lab.
Pepsinogen-derived fragments as antibiotic candidates:
Pepsinogen is an enzyme required to break down proteins in the stomach. Pepsinogen, which is secreted by cells lining the stomach, is inactive by itself. In the stomach, hydrochloric acid mixes with pepsinogen, converting it into the active proteolytic enzyme pepsin A and several other small fragments. These fragments, which are byproducts of the digestion process, had no known functions until now. They turned out to be candidates in the antimicrobial screen.
The lab tests showed that the three peptides were effective against a wide range of bacteria, including foodborne pathogens such as Salmonella and E. coli, as well as Pseudomonas aeruginosa, which infects the lungs of cystic fibrosis patients. Moreover, the peptides were active against multi drug-resistant strains of bacteria.
Successive experiments in a mouse model showed that one of the fragments, (P)PAP-A3, could significantly reduce skin infections caused by Pseudomonas aeruginosa. (P)PAP-A3, therefore, has emerged as a promising antibiotic drug candidate. While less powerful, the other two fragments were still effective in reducing the bacteria numbers by two orders of magnitude. Importantly, none of the fragments exhibited any toxicity to human cells, and the effects were observed at both neutral pH and at an acidic pH similar to the stomach. The team’s studies also demonstrate that other pepsinogens or pepsinogen-derived fragments may have similar antimicrobial properties.
Mode of action:
The mechanism by which these fragments act on the microbes is not understood clearly. The researchers hypothesize that the positive charges in these peptide fragments could help them bind to the negatively charged bacterial membranes and poke gaps in them, akin to other antimicrobial peptides.
A step ahead of antibiotic resistance:
These peptides are an excellent template for engineering. The next step is to use synthetic biology to modify the fragments to make them even more potent. Modification of these peptides could increase their antimicrobial activity.
The team intends to investigate other candidates found by the algorithm for antimicrobial activity. The idea is to test if each of these compounds could get developed into a new antibiotic.
The researchers are also searching for new potential peptides from organisms other than humans for use as antibiotics. By adopting the computational approach taken in this study, scientists could discover new AMPs from previously unexplored sources.
It has been estimated that antimicrobial drug resistance could cause more than ten million deaths every year worldwide by 2050. The new class of peptides derived from pepsinogen holds tremendous potential and could give us an edge in the race against antibiotic resistance.
