Defense Media Network

VA Research: Drug-resistant Infectious Diseases

“One of the biggest areas of research over the last 10 years that has transformed cancer treatment, to some degree,” said Robert Striker, M.D., Ph.D., associate professor at the University of Wisconsin School of Medicine and a researcher with the William S. Middleton Memorial Veterans Hospital, “has been a class of drugs called kinase inhibitors.” Kinase, an enzyme, works as a kind of switch to turn certain cell functions, such as protein formation, on or off. In cancer cells, kinases have become “dysregulated,” leading to unchecked cell growth. Kinase inhibitors target this dysregulation, essentially turning the switch to the “off” position.

In some cases, promising treatments have been suggested by findings in cancer research.

According to Striker, there are more than 500 kinases at work in human cells, and cancer researchers have so far formulated about 25 FDA-approved kinase inhibitors that will target specific switches on cancer cells, slowing or stopping tumor growth while leaving the rest of the body’s cells alone. In his laboratory, Striker’s team has discovered that some of these drugs can hit a kinase switch on the MRSA organism and re-sensitize it to methicillin, which kills S. aureus by preventing it from building a cell wall.

C diff VAMM18B web

An illustration of Clostridium difficile, or C. diff. The bacteria is often spread in health care facilities, like hospitals or nursing homes. Image by Kateryna Kon

Methicillin is one of a family of antibiotics known as the beta-lactams, commonly denoted as β-lactams, which also include penicillins, cephalosporins, carbapenems, and monobactams. One of the oldest and most successful classes of antibiotics, the β-lactams have also contributed significantly to the evolution of drug resistance among pathogenic organisms. Striker and his team have used kinase inhibitors to re-sensitize other organisms, such as Streptococcus pneumoniae and Listeria monocytogenes, to β-lactams.

The switch targeted by Striker is known as the PASTA kinase: “A penicillin-associated serine/threonine kinase,” said Striker. “The acronym doesn’t quite work.” It’s unique to Gram-positive organisms, including some, such as tuberculosis, that haven’t been treated with β-lactam antibiotics in the past – but which can be made sensitive to them now, Striker said, with the use of kinase inhibitors. “We’re not just creating new antibiotics,” he said, “but we’re creating antibiotics that will rescue some of the old antibiotics and make them more active against bacteria that contain these PASTA kinases.”

In her work as chief of the Division of Infectious Disease at the Stony Brook University School of Medicine and as a researcher with the Northport VA Medical Center, Bettina Fries, M.D., has studied the effectiveness of fighting Klebsiella pneumoniae, the most common drug-resistant Gram-negative bacterium, with a cancer treatment pioneered by Nobel laureates in the 1970s: hybridoma technology, which boosts the immune system’s ability to attack and kill invasive cells.

“We’re not just creating new antibiotics,” he said, “but we’re creating antibiotics that will rescue some of the old antibiotics and make them more active against bacteria that contain these PASTA kinases.”

When an animal is injected with a substance that provokes an immune response, specialized white bloods cells known as B cells produce antibodies that bind to the injected antigen, and then antibody-producing B cells are then harvested from the spleen of the animal – typically, a mouse. These B cells are then fused with mutated B cells known as myelomas, producing a cell line called a hybridoma, which both produces antibodies and reproduces like a cancer cell. These hybridomas, also known as monoclonal antibodies, are chemically identical and built to target specific cells.

Klebsiella is an organism that’s often harmless, commonly found on the skin or in the mouth or gut, but can turn virulent and, when found in the lungs, is a major cause of HAIs. It has developed a resistance to broad-spectrum carbapenems, one of the last lines of defense in treating MDROs in hospital patients, and is associated with high mortality rates.

acinetobacter bacteria VAMM18B web

A 3-D computer-generated image of a group of multidrug-resistant Acinetobacter bacteria. CDC/James Archer

Fries and her colleagues are studying ways to get around this drug resistance by boosting the body’s own immune response, creating monoclonal antibodies that target the polysaccharide capsule of Klebsiella, part of the bacterium’s outer envelope. “When the antibody binds to the bacteria, then the bacteria are taken up by inflammatory cells in the patient and killed,” said Fries.

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Craig Collins is a veteran freelance writer and a regular Faircount Media Group contributor who...