Research from a five-year study conducted by investigators at NYU Grossman School of Medicine and Janssen Biotech has demonstrated, in early tests, that a bioengineered drug candidate has shown superior performance treating Staphylococcus aureus compared with standard antibiotic treatment, including the treatment-resistant form MRSA (methicillin resistant Staphylococcus aureus).
In a paper published today in the journal Cell & Host, researchers detail early testing of the mAbytrins, a combinantion molecule that is built on an engineered version of a human monoclonal antiboy (mAb), a protein that attaches to S. aureus and marks it for elimination by immune cells. The mAbs have a type of protein called cyterins attached to them. Cyterins prevent the bacteria from boring holes in the human immune cells where they hide. As the invaders multiply, these cells burst illuminating their threat to the bacteria.
The experimental treatment, SM1B74, targets ten disease-cause mechanism of S. aureus, but don’t kill it. By not killing the bacteria, the researchers say they may have developed an approach to overcoming antibiotic resistance which occurs when antibiotics kill the most vulnerable strains first, leaving more room for strains that happen to be less vulnerable. Those strains surviving are the reason for the development of antibiotic resistance.
“To our knowledge, this is the first report showing that mAbtyrins can drastically reduce the populations of this pathogen in cell studies, and in live mice infected with drug-resistant strains so common in hospitals,” said lead study author Victor Torres, PhD, the C.V. Starr Professor of Microbiology and director of the NYU Langone Health Antimicrobial-Resistant Pathogen Program. “Our goal was to design a biologic that works against S. aureus inside and outside of cells, while also taking away the weapons it uses to evade the immune system.”
The new research caps five years of work via a partnership between NYU Langone and Janssen Biotech that has delved into better understanding the nature of S. aureus and its ability to develop drug resistance. In 2019, this collaboration yielded a 2019 paper that described how centyrins interfere with the action of toxins used by S. aureus to bore into immune cells. To develop candidate centyrins that might cling more tightly to toxins blocking their function, the team made used a molecular biology technique to make changes, via automation, to a single parental centyrin that created a trillion slightly different versions.
For their new research, the team used this prior knowledge to fuse centyrins to a mAb from a patient recovering from an S. aureus infection. Since this mAb was already primed from its exposure to the bacteria, the mAb could label the bacterial cells so that they would be pulled into bacteria-destroying pockets inside of roving immune cells called phagocytes. That is unless the same toxins that enable S. aureus to drill into immune cells from the outside let it drill out of the pockets to invade from the inside.
In what the authors describe as a “marvel of bioengineering” part of mAbytrin serves as the passport recognized by immune cells, which then engulf the entire attached mAbtyrin, along with its centyrins, and fold it into the pockets along with bacteria. Once inside, the centyrins block the bacterial toxins. Targeting the toxins within the cells is what differentiates this approach, from those used previously to treat infection, which have focused on targeting the toxins outside the cell.
The team made other changes to their mAbytrin specifically aimed at those that defeat S. aureus, including activating chain reactions that amplify the immune response, as well by preventing certain bacterial enzymes from cutting up antibodies and others from interfering with their action.
To test their engineered candidate the team tracked commonly occurring strains of S. aureus common in communities in the U.S. in the presence of phagocytes. Populations of the bacteria grew normally in the presence of the parental antibody, with slight less growth in the presence of the engineered mAb, and remarkably half as fast when mAbytrin was used.
A second test showed that in 98% of mice treated with a control mAb developed bacteria-filled sores on the kidneys when infected with S. aureus while only 38% percent of mice developed them when treated with mAbytrin. Tissue samples showed a stark difference as well: the mice treated with mAbytrin has one hundred times fewer bacterial cells than those treated with the control.
To cap their research, the investigators then paired mAbytrin with small doses of the antibiotic vancomycin in mouse studies and found that the combination resulted in maximum reduction of bacterial loads in the kidney and more than 70% greater protection from kidney lesions.