New methods to develop novel antibiotics are desperately needed to treat antibiotic-resistant “superbugs.” Now, researchers at the Keck School of Medicine of USC report they have developed a new bio-inspired molecule that is effective in clearing bacterial infections in an animal model. The molecule acts as an immune stimulant instead of an antibiotic, presenting a new way to treat antibiotic-resistant infections.

Their findings are published in the journal Scientific Reports in an article titled, “A host-directed macrocyclic peptide therapeutic for MDR gram negative bacterial infections,” and led by Justin Schaal, PhD, an assistant professor of research pathology at the Keck School of Medicine.

“The emergence of infections by carbapenem resistant Enterobacteriaceae (CRE) pathogens has created an urgent public health threat, as carbapenems are among the drugs of last resort for infections caused by a growing fraction of multi-drug resistant (MDR) bacteria,” the researchers wrote. “There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. Here, we report on the efficacy of a novel macrocyclic peptide, minimized theta-defensin (MTD)-12813 in CRE sepsis.”

Antibiotics have been the standard of care for bacterial infections. Despite dozens of varieties, almost all work by killing bacteria directly or by blocking their ability to proliferate.

“This is the root cause of antibiotic resistance,” Schaal said. “Bacteria have an immense ability to evolve rapidly, which gives them power to overcome direct-acting antibiotic molecules.”

The researchers bioengineered molecules and screened them for their ability to fight Klebsiella infections in a mouse model. The most potent peptide they created was a highly stable cyclic peptide called MTD12813.

More research is needed to determine exactly how MTD12813 works, however, the researchers know it activates macrophages and neutrophils in the immune system. The peptide also modulates the immune response, reducing poorly regulated inflammation.

“We call this peptide a host-directed anti-infective because rather than kill the bacteria directly like traditional antibiotics, it stimulates the host—us—to fight the infection,” Schaal said.

Through a licensing agreement with USC, the technology will now be developed further in partnership with Oryn Therapeutics.

“Based on this and related research conducted at USC, Oryn is developing a novel class of macrocyclic peptides as therapeutics for unmet needs in autoimmune and inflammatory diseases, infectious diseases, and cancer. We are quite optimistic about the prospects for turning the important scientific advances reported in this publication into successful treatments for increasingly dangerous bacterial infections,” said Robert Erwin, Oryn’s CEO.

“This new discovery of how to stimulate host clearance of bacteria is really timely,” he added.

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