Saving the medicine of last resort

Author: John Monczunski

Unless you’ve been at death’s door with a compromised immune system or happen to be a medicinal chemist, chances are you’ve never heard of a “carbapenem” antibiotic. But should you have the misfortune to become gravely ill with an infection and no other medicine works, you’ll be glad to come in contact with one. When all else fails, these antibiotics are the last bullet in the gun.

The problem is that carbapenems, like all antibiotics, are slowly losing their punch. And that’s where ND’s Sergei Vakulenko comes in. The associate research professor of chemistry and biochemistry, who holds an M.D. as well as Ph.D., is focused on learning whatever it takes to keep these drugs potent.

Unfortunately, some bacteria possess certain enzymes that naturally inactivate the most widely employed antibiotics, the so-called “beta-lactam” antibiotics, which include the penicillins, cephalosporins and carbapenems. Ever since the original penicillin was introduced during World War II, natural selection has favored those bacteria that have the enzymes to kill any new antibiotic which is developed, Vakulenko says. “Modification mutation happens very fast. Sometimes as quickly as just within a few months of clinical introduction. The bacteria outsmart us every time.”

The enzymes that destroy the carbapenems are known as carbapenemases. Unfortunately, these enzymes began to appear about 15 years ago and are becoming more widespread, the ND chemist says. Carbapenemases make the bacteria resistant by breaking up the ring structure of the last-result antibiotic; opening it up makes it ineffective, Vakulenko explains.

The Notre Dame research chemist and his colleagues are studying the carbapenemases to provide basic scientific knowledge that later might be used to develop novel antibiotics or inhibitors of the enzymes. Among other things, Vakulenko’s group is conducting “kinetic” studies of the enzymes, which in detail describe at the molecular level what happens to the antibiotic when it encounters the enzyme. The researchers attempt to discover how the reaction proceeds, how fast it occurs and exactly what steps are involved in the inactivation of the antibiotic.

Vakulenko’s group also examines the structure of the enzymes, using X-ray analytical techniques. The work is vital because if the structure of the enzyme can be determined as the antibiotic attaches to an active site of one of the enzymes, that provides the critical knowledge for chemists to develop new, potent antibiotics.

John Monczunski is an associate editor of Notre Dame Magazine.