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Antibiotic-releasing polymer eliminates prosthetic infection, antimicrobial peptide polymers destroy bacteria

Antibiotic-releasing polymer eliminates prosthetic infection, antimicrobial peptide polymers destroy bacteria

03-Aug-17

An antibiotic-releasing polymer that may greatly simplify the treatment of prosthetic joint infection has been developed by a team of Massachusetts General Hospital (MGH) investigators. In their report published in Nature Biomedical Engineering, the researchers describe how implants made from this material successfully eliminated two types of prosthetic infection in animal models.
Currently, most infections involving total joint replacement prostheses require a two-stage surgery, in which the patient's daily activities are largely compromised for 4-6 months. Delivering antibiotics to an infected prosthetic joint is challenging because of the limited supply of blood to the area. The standard treatment for prosthetic joint infection in the U.S.  involves removal of the implant and adjacent infected tissues and placement of a temporary spacer made from antibiotic-releasing bone cement that remains within the joint space for at least six weeks and sometimes for as long as six months. During that time, the patient's movement may be significantly restricted, depending on the involved joint. In a second surgery, a new prosthesis is implanted, using antibiotic-releasing bone cement. But patients still can be at risk for recurrent infection, which may lead to the need for permanent joint fusion or amputation and has a 10-15% mortality rate. Antibiotic-releasing bone cement has several limitations. Its ability to release an effective antibiotic dose may be brief, lasting little more than a week, and increasing the antibiotic content reduces the material's durability. In addition, some antibiotics with desirable qualities cannot be incorporated into a bone cement. For the current study, the research team - including lead author Jeremy Vincentius Suhardi, a Harvard/MIT MD/PhD student, and senior author Ebru Oral, PhD, both of the Harris Lab - designed and developed an antibiotic-releasing polymer that could be incorporated into the implant itself.
Based on mathematical and statistical models, the material they developed contained antibiotic clusters which were irregularly shaped, making them able to release effective drug doses over extended periods of time without compromising the strength of the material. Implants made from this polymer were tested in animal models of prosthetic joint infection produced either by injecting a Staph. aureus-containing solution into the prosthesis or implanting a titanium rod covered with a Staph. Aureus biofilm, a coating of bacteria that is particularly difficult to treat. In both situations, the antibiotic-releasing polymer successfully eliminated the infection, while implantation of a drug-release bone cement spacer was not effective. "We used two separate infection models because, when patients present with prosthetic joint infection symptoms, it is not clear what proportion of bacteria may be in a biofilm and what are free floating in solution," says Muratoglu. "The ability of our devices to eradicate all bacteria in the joints in both models strongly suggests they would be successful against both types of periprosthetic infection." A professor of Orthopedic Surgery at Harvard Medical School, Muratoglu notes that, in addition to speeding the recovery of patients and reducing the chance of complications, the elimination of a second surgical procedure should reduce overall costs. The team is now working with the Food and Drug Administration and other regulatory agencies to pursue necessary approvals and develop this material into clinical products.

Antibiotic-resistant ‘superbugs’ could soon be a thing of the past after a team of Australian scientists discovered a protein that literally rips them apart. The team including Qiao, Eric Reynolds, and PhD candidate Shu Lam- published a paper in Nature Microbiology describing a promising alternative technology to combat multidrug-resistant bacteria. Instead of designing a traditional chemical drug treatment, the team developed what they call structurally nano engineered antimicrobial peptide polymers (SNAPPs). The researchers were inspired by natural antimicrobial peptides, which are small proteins that play important roles in the immune systems of many organisms. The scientists meticulously designed the polymers, down to the level of the individual building blocks- amino acid, that would make up the peptides.
Out of the many amino acids available to them, the scientists chose lysine and valine. Lysine is a positively charged cation, and was selected because cationic peptides were already known to exhibit antimicrobial activity. Valine, on the other hand, is uncharged and therefore hydrophobic, meaning it does not interact favorably with water or other polar molecules. Since hydrophobic materials interact favorably with other hydrophobic materials, valine’s hydrophobicity enables the SNAPPs to infiltrate the cell membrane, which is also mostly hydrophobic. Instead of just creating long chains of amino acids or allowing the polymers to self-assemble, the researchers attached groups of 16 or 32 chains to a multifunctional core, which served to promote water solubility and create the characteristic star shape. They hypothesize that the star shape optimizes functionality because it promotes peptide aggregation and localized charge concentration, which leads to more effective ionic interactions with bacterial membranes.
The researchers assessed the activity of the SNAPPs against different species of bacteria. The SNAPPs were active against all bacterial species but were especially effective against Gram-negative bacteria like E. coli. Gram-negative bacteria are characterized by an outer membrane that normally acts as a highly impermeable barrier, but the researchers discovered that the SNAPPs could penetrate this membrane since they have a high affinity for specific molecules found on it. The treatment was equally effective against antibiotic-resistant and susceptible strains of bacteria. The effectiveness of SNAPPs against Gram-negative bacteria is especially important because no antibiotic drugs currently under development are effective against Gram-negative infections.
The SNAPPs have multiple mechanisms of killing cells, making it more difficult for bacteria to develop resistance against them. The polymers’ partially hydrophobic composition allows them to infiltrate the membrane, but once they have done so, the positively charged amino acids disrupt membrane integrity and prevent regulation of ion flow. The star-shaped polymers can even aggregate and rip apart the membrane. The SNAPPs may also trigger the cellular processes that induce apoptosis, or cell suicide. All these mechanisms of antibiotic action are impressive individually, but when combined in a single molecule they are incredibly powerful and difficult for bacteria to fight. Even after exposing 600 generations of bacteria to low concentrations of SNAPPs, the researchers could not detect bacterial resistance to the treatment. These results show great promise for SNAPPs as a long-term solution to the rise of superbugs.
To bring treatments like SNAPPs into regular use, more research, development, and eventually clinical trials are needed.

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