An engineered peptide provides a new prototype for killing an entire category of resistant bacteria by shredding and dissolving their double-layered membranes, which are thought to protect those microbes from antibiotics.
The synthetic peptide was effective in lab experiments against antibiotic-resistant Gram-negative bacteria, which cause a variety of difficult-to-treat, potentially lethal infections such as pneumonia and sepsis.
The team led by scientists at The University of Texas MD Anderson Cancer Center reported its findings online in advance of print this week at the Proceedings of the National Academy of Science.
"The antibiotic pipeline against multidrug-resistant Gram-negative problem pathogens is a major unmet need in contemporary medicine; as such, our new antimicrobial agent holds immediate promise," said co-senior author Wadih Arap, M.D., professor in MD Anderson's Department of Genitourinary Medical Oncology and the David H. Koch Center.
Arap, Renata Pasqualini, Ph.D., also a co-senior author, professor in genitourinary medical oncology and the Koch center, and colleagues have previously constructed peptide combinations that are in development against cancer and white fat cells.
"The prototype introduced here as an antibiotic candidate has a unique mechanism of action and translational applications readily identified," Pasqualini said.
Gram-negative bacteria that are highly resistant to existing treatments include E. coli, Acinetobacter baumanii, Pseudomonas aeruginosa, and kebsiella pneumonia. These infections are often present in health care settings and most threatening to people with weakened immune systems.
The spiral peptide called KLAKLAKKLAKLAK acts against bacteria by puncturing their lipid bilayer membranes and has only low toxicity toward mammalian cells. These antimicrobial peptides, however, are subject to routine destruction by host enzymes or those generated by the microbe. Combating that effect by increasing the dose heightens both toxicity to other cells and cost.
D- KLAKLAKKLAKLAK destroys microbes, biofilms
Arap, Pasqualini and colleagues engineered a version of KLAKLAKKLAKLAK to use in their combination therapies but had not tested the peptide alone as an antibiotic.
The peptide is made of L-amino acids, the building blocks of life, which makes them vulnerable to destruction. The researchers synthesized a peptidomimetic – a version of the peptide using D-amino acids with a reversed peptide sequence, making it more durable.
In a series of lab experiments, the researchers found that D-KLAKLAKKLAKLAK:
Next step: Animal model experiments
Arap and Pasqualini note that developing D- KLAKLAKKLAKLAK as a drug will next require experiments in animal models of sepsis and other infections to further gauge the peptide's effectiveness and side effects.
In their cancer and anti-obesity research, the D-peptide is used with targeting agents to hit specific cells. Large preclinical studies in mice, rats and monkeys showed low toxicity at treatment-level concentrations. Their cancer drug in a first-in-human phase I clinical trial revealed side effects that were predictable, dose-dependent and reversible. Even so, toxicity may differ when it's used against bacterial infections.
The peptide was not effective against Gram-positive bacteria, which have thicker cell walls but are generally more vulnerable to antibiotics and the immune system than are Gram-negative bacteria. Gram-positive bacteria include those that cause anthrax, tuberculosis, strep throat and such treatment-resistant infections as Staphylococcus aureus.
Gram-negative bacteria, which have thinner membranes but are generally more resistant to antibiotics or immune system attack, also include those that cause typhoid fever, cholera, gonorrhea, syphilis and lyme disease.
University of Texas M. D. Anderson Cancer Center: http://www.mdanderson.org
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Is there a conscious generosity in how ravens or bats share food, or monkeys or elephants save others, or is it simply the selfish instinct of group survival?
DNA research into early canine remains also raises clues about migration patterns of ancient humans
Research on 85 families finds less than a third of siblings with autism carry the same genetic risk, and in nearly 70% of cases known contributory mutations do not overlap
Flanked by curious fish and tended by a diver, these coral nurseries off the coast of the Florida Keys are being grown as transplants for damaged reefs
If we could turn back the clock millions of years, would animals evolve in the same way? Genome data suggests that their options would be limited
Ah, motherhood. I don’t know anything about it, but I heard there’s a lot of, like, sacrifice and stuff. Not only do you have to bring the brat into the world, but then you have to feed it for at least 18 years or you get in big trouble. That’s a lot of pressure.
It’s three in the morning in South Africa, in the middle of winter. Temperatures have dropped to just …
A jellyfish tagging study reveals the creatures' ability to swim against the current when forming their submarine swarms, say researchers.
Size isn't everything. When many male mice mate with the same females, their descendants evolve testes that can produce more sperm
Along the seashore, harmful blooms caused by an organism called Sea Sparkle choke ecosystems but look positively enchanting