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.
Results of largest ever genetics study of a single population could also help refine dates for major events during human evolution Humans are evolving more rapidly than previously thought, according to the largest ever genetics study of a single population.
Latest genetic tests reveal another break in the male line, potentially undermining the legitimacy of the entire House of Plantagenet When scientists revealed last year that an adulterous affair had apparently broken the male line in Richard III’s family tree, they vowed to investigate further.
By 2016, Icelandic genetics company deCODE will have data on half the country's population. Releasing the data will be controversial, but could save lives
A clinical trial has shown that the drug aducanumab slows cognitive decline in people with Alzheimer's and reduces the amount of amyloid plaque in their brain
A leading researcher issues a call for pills that deliver a full course of treatment in one swallow.One of the world’s preëminent biomedical researchers is calling for a concerted effort by scientists to develop pills that would stay in the stomach or gut for weeks or months once swallowed, delivering one or more drugs continuously or over set intervals.
Two genes responsible for building up drug-resistance can easily be shared between a family of bacteria
When malaria parasites infect blood, they manufacture odor molecules that smell sweet to mosquitoes, scientists report. So how do these odors get from the bloodstream to the insects?
Researchers are developing new method of wireless deep brain stimulation.
Zoos belonging to World Association of Zoos and Aquariums filmed allowing shocking mistreatment of elephants, dolphins, lions, bears, penguins and whales
Owners of Highland Wildlife Park hope Victoria, 18, will get chummy with male Arktos during her stay in the Cairngorms