Synthetic Peptide Drug Overcomes Bacterial Resistance to Antibiotics

A team of molecular microbiologists has demonstrated the potential value of engineered cationic antibiotic peptides (eCAPs) for treating infections caused by bacteria that have developed resistance to traditional antibiotics.

Cationic antimicrobial peptides (CAPs) are amphipathic peptides of 12–50 amino acids with a net positive charge. They are ubiquitous peptides naturally found in all living species and are known to be active components of the innate immunity against infectious pathogens. In response to infectious pathogens, CAPs can be released from macrophages, granules of neutrophils, or with mucosal and skin secretions from epithelial cells. CAPs can act against a wide range of targets including gram-positive and gram-negative bacteria, fungi, and parasites. The only essential component in these targets is a negatively charged plasma membrane. Therefore, normal cells have a relative resistance due to the peptides preference for negatively charged, cholesterol free membranes.

The mechanism of action of CAPs is not fully understood, although studies have implicated the electrostatic interaction between the peptides and the lipid molecules on the bacterial membrane. When compared to other antibiotics, CAPs are able to kill bacteria rapidly, within 30 to 180 seconds, limiting the bacterium’s ability to develop resistance against these peptides. Therefore, CAPs are considered a good candidate for use against multi-drug resistance (MDR) bacteria. Engineered cationic antimicrobial peptides or eCAPs represent a subclass that is chemically synthesized in a laboratory setting.

Investigators at the University of Pittsburgh School of Medicine (PA, USA) compared two eCAPs, WLBU2 and WR12, to the natural antimicrobial peptide LL37 and to the standard antibiotic colistin for the ability to overcome resistance to antibiotics.

In this study the investigators worked with 100 different bacterial strains isolated from the lungs of pediatric cystic fibrosis patients from Seattle Children's Hospital and 42 bacterial strains isolated from hospitalized adult patients at the University of Pittsburgh School of Medicine.

Results published in the November 24, 2014, online edition of the journal Antimicrobial Agents and Chemotherapy revealed that while LL37 and colistin each inhibited growth of about 50% of the clinical isolates (indicating a high level of bacterial resistance to these drugs), the two eCAPS inhibited growth in about 90% of the test bacterial strains.

"Very few, if any, medical discoveries have had a larger impact on modern medicine than the discovery and development of antibiotics," said senior author Dr. Ronald C. Montelaro, professor of microbiology and molecular genetics at the University of Pittsburgh School of Medicine. "However, the success of these medical achievements is being threatened due to increasing frequency of antibiotic resistance. It is critical that we move forward with development of new defenses against the drug-resistant bacteria that threaten the lives of our most vulnerable patients."

"We were very impressed with the performance of the eCAPs when compared with some of the best existing drugs, including a natural antimicrobial peptide made by Mother Nature and an antibiotic of last resort," said Dr. Montelaro. "However, we still needed to know how long the eCAPs would be effective before the bacteria develop resistance. We plan to continue developing the eCAPs in the lab and in animal models, with the intention of creating the least-toxic and most effective version possible so we can move them to clinical trials and help patients who have exhausted existing antibiotic options."

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University of Pittsburgh School of Medicine