Researchers from NYU Grossman School of Medicine and Janssen Biotech, Inc. have shown in early testing that a bioengineered drug candidate can counteract infection with staphylococcus aureus — a bacterial species widely resistant to antibiotics and a leading cause of death in hospitalized patients.
Experiments demonstrated that SM1B74, an antibacterial biologic agent, was superior to a standard antibiotic drug in treating mice infected with S.aureusincluding its treatment-resistant form known as MRSA.
Posted online April 24 in host cell and microbe,The new paper describes the first tests of mAbtyrins, a combination molecule based on an engineered version of a human monoclonal antibody (mAb), a protein that binds to and marks S.aureus for uptake and destruction by immune cells. Attached to the mAb are centyrins, small proteins that prevent these bacteria from piercing the human immune cells in which they hide. As the invaders multiply, these cells die and burst, removing their threat to the bacteria.
Taken together, the experimental treatment targets ten disease-causing mechanisms employed by S.aureus, but without killing it, say the study authors. This approach holds promise for tackling antibiotic resistance, the researchers say, where antibiotics kill vulnerable strains first, only to leave more room for others that turn out to be less vulnerable until the drugs no longer work.
“To our knowledge, this is the first report showing that mAbtirins can dramatically reduce populations of this pathogen in cell studies and in live mice infected with drug-resistant strains so common in hospitals,” said the study’s lead author. , Victor Torres, PhD, the CV Starr Professor of Microbiology and Director of the Langone Health Antimicrobial Resistant Pathogens Program at NYU. “Our objective was to design a biological product that acts against S.aureus inside and outside of cells, while eliminating the weapons it uses to evade the immune system.”
One third of the human population are carriers of S.aureus without symptoms, but those with weakened immune systems can develop life-threatening lung, heart, bone, or bloodstream infections, especially among hospitalized patients.
Inside out
The new study is the culmination of a five-year research partnership between scientists at NYU Grossman School of Medicine and Janssen to address the unique nature of S.aureus.
The NYU Langone team, together with researchers from Janssen, published a study in 2019 that found that centirins interfere with the action of potent toxins used by S.aureus pierce immune cells. They used a molecular biology technique to make changes to a single parent centirine, instantly creating a trillion slightly different versions through automation. Outside of this “library,” careful examination revealed a small set of centirins that bind more strongly to toxins that block their function.
Building on this work, the team fused the centirins with an mAb originally taken from a patient recovering from S.aureus infection. Already primed by its encounter with bacteria, the mAb could tag bacterial cells in such a way that they are drawn into bacteria-killing pockets within roving immune cells called phagocytes. That is unless the very toxins that allow S.aureus to pierce immune cells from the outside, let it pierce the pockets to invade from the inside.
In a “marvel of bioengineering,” part of the team’s mAbtirin serves as a recognized passport for immune cells, which then gobble up all the attached mAbtirin, along with its sentirins, and fold it into their pockets along with the bacteria. Once inside, the sentirines block the bacterial toxins there. This, the authors say, sets their effort apart from antibody combinations that target toxins only outside of cells.
The team made several additional changes to their mAbtyrin which they defeated S.aureus for example, activating chain reactions that amplify the immune response, as well as preventing certain bacterial enzymes from cutting off the antibodies and others from hindering their action.
In terms of experiments, the researchers tracked the growth of S.aureus strains that commonly occur in American communities in the presence of primary human immune cells (phagocytes). Bacterial populations grew almost normally in the presence of the parental antibody, slightly less so in the presence of the team’s designed mAb, and half as fast when mAbtyrin was used.
In another test, 98% of mice treated with a control mAb (no centirines) developed bacteria-filled sores on their kidneys when infected with a deadly strain of S.aureus, whereas only 38% of the mice did so when treated with mAbtyrin. Furthermore, when these tissues were removed and the bacterial colonies in them were counted, mAbtyrin-treated mice had one hundred times (two logarithms) fewer bacterial cells than those treated with a control mAb.
Finally, combining small doses of the antibiotic vancomycin with mAbtyrin in mice significantly improved the efficacy of mAbtyrin, resulting in maximal reduction of bacterial loads in the kidneys and greater than 70% protection against kidney injury.
“It’s incredibly important,” Torres said, “that we find new ways to enhance the action of vancomycin, a last line of defense against MRSA.”
Along with Torres, the authors from the NYU Langone Department of Microbiology were Rita Chan, Ashley DuMont, Keenan Lacey, Aidan O’Malley, and Anna O’keeffe. The study authors included 13 scientists from Janssen Research & Development (for details, see the study manuscript).
This work was supported by Janssen Biotech, Inc., one of Johnson & Johnson’s Janssen Pharmaceutical Companies, under the auspices of an exclusive license and collaborative research agreement with NYU. Torres has recently received royalties and consulting compensation from Janssen and related entities. These interests are managed in accordance with NYU Langone’s policies and procedures.
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