Navigation Links
Synthetic corkscrew peptide kills antibiotic-resistant Gram-negative bacteria
Date:1/24/2013

HOUSTON 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:

  • Kills a variety of strains of E. coli, A. baumanii and P. aeruginosa, including multi-drug resistant strains.

  • Works against Gram-negative bacteria at all phases of growth, including dormant cells that are prone to become resistant.

  • Causes dose-dependent damage to the bacterial membrane resulting in its dissipation and cell death.

  • Specifically disrupts lipids found in Gram-negative bacteria membranes while not affecting membranes in eukaryotic cells cells with the nucleus and other structures enclosed in separate membranes found in mammals and other non-microbial life.

  • Works in combination with the antibiotic piperacillin at lower doses to kill bacteria.

  • Eliminates biofilms, layers of combinations of microbes that adhere to surfaces and provide an ideal setting for bacterial growth.

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.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

Related medicine news :

1. Biosynthetic grape-derived compound prevents progression of Alzheimers disease in mice
2. Stimulant marketed as natural in sports supplement actually of synthetic origin
3. Synthetic stimulants called bath salts act in the brain like cocaine
4. Scientists explore new class of synthetic vaccines
5. Boston University researchers expand synthetic biologys toolkit
6. Synthetic Skin Heals Itself With a Touch, Study Shows
7. Researchers build synthetic membrane channels out of DNA
8. Probiotic Action Issues a Response to an Article on Medical News Today About Synthetic Skin Research
9. Synthetic Pot Sending Thousands of Young People to ER: Report
10. Strange behavior: New study exposes living cells to synthetic protein
11. Combination peptide therapies might offer more effective, less toxic cancer treatment
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/27/2016)... (PRWEB) , ... May 27, 2016 , ... ... this installment is bolstered by inspiring human interest stories, courtesy of leaders in ... trends and tech within the industry, from leading advocates and associations—namely Jones & ...
(Date:5/26/2016)... ... May 26, 2016 , ... Despite last week’s media reports ... Yellen and company to wait until March 2017 for an interest rate increase, according ... Robinson College of Business. , “The Federal Open Market Committee (FOMC) dot charts are ...
(Date:5/26/2016)... ... May 26, 2016 , ... Intalere, the healthcare ... suppliers for its inaugural Member Conference at the Paris Hotel in Las Vegas, ... operational health of America’s healthcare providers. , The conference was highlighted by the ...
(Date:5/26/2016)... ... ... The Woodlands at John Knox Village , Florida’s first Life Plan ... and healing, celebrated its grand opening, today. The Woodlands at John Knox Village is ... Staff. , “This is an incredibly fulfilling time for John Knox Village as we ...
(Date:5/26/2016)... ... May 26, 2016 , ... ... solutions for drugs, biologics, consumer health and global clinical supply services, today announced ... to support the company’s continued investment and strategic growth plans in the Asia ...
Breaking Medicine News(10 mins):
(Date:5/24/2016)... , May 24, 2016  Joe Marziani has joined VMS BioMarketing as senior ... executive officer, today. In his new role, Marziani will lead the company,s business development ... professionals to improve outcomes. Photo - http://photos.prnewswire.com/prnh/20160523/371089 ... ... ...
(Date:5/24/2016)... KONG , May 24, 2016 ... stent de doble terapia del mundo, introduce catéteres ... arteriovenosa. OrbusNeich, una compañía global especializada ... las vidas, ha expandido su cartera incluyendo productos ... balón JADE™ y Scoreflex™ PTA son los dispositivos ...
(Date:5/24/2016)... -- Open Access Journal Focusing on ... Elsevier , a world-leading provider of scientific, technical ... launch of Clinical Neurophysiology Practice ... clinical practice issues in clinical neurophysiology. The journal will ... and didactic reviews. It is an official journal of ...
Breaking Medicine Technology: