If you have had strep throat or an ear infection, there's a good chance you received amoxicillin or penicillin to effectively kill the troublesome bacteria.
These drugs, which belong to a broad group of antibiotics called beta-lactams, are commonly used to treat various bacterial infections, from urinary tract infections to pneumonia and sepsis.
But beta-lactam antibiotics can-and do-fail, even in the absence of antibiotic resistance.
Researchers at the UNC School of Medicine have pinpointed a specific protein within our immune system that interferes with the antibiotic's ability to kill bacteria. Their results are further explained in a paper published in the Proceedings in the National Academy of Sciences.
"We found that a major innate immune protein sequesters essential metals, which can inadvertently allow the bacteria to survive our most widely used antibiotic class," said Brian Conlon, PhD, associate professor of microbiology and immunology at the UNC School of Medicine and senior author on the paper. "This is an unfortunate antagonism between beta-lactam antibiotics and our immune system that may be driving clinical failure."
What is Antibiotic Tolerance?
Brian Conlon, PhD
Antibiotic tolerance poses a great risk to patients with severe and reoccurring infections, as bacteria can withstand strong doses of antibiotics.
About 20% of patients with MSSA (methicillin sensitive Staphylococcus aureus) infections treated with oxacillin die. These outcomes are tied and to antibiotic tolerance, where pathogens are able to survive the killing activity of the antibiotic for extended periods.
To better understand why antibiotic tolerance occurs in such commonly used antibiotics, Conlon and his lab have been on a years-long mission to understand what, within our own immune system, may be interfering with antibiotic action, in addition to the pathogens themselves.
Beta-lactam antibiotics work by attacking the outer protective layer of bacterial cells, known as the cell wall. When antibiotics damage this layer, bacterial enzymes called autolysins begin to eat the wall, causing it to disintegrate completely and the bacterial cell to rupture. This process is what ultimately kills entire bacterial colonies and prevents further infection.
The Findings
Led by Amanda Z. Velez, an MD/PhD candidate in the Conlon lab, researchers decided to focus on calprotectin, a powerful protein within our immune system that serves as one of the body's "first responders" at infection site(s). Researchers set up a study of Staphylococcus aureus to understand how calprotectin impacts antibiotic activities.
Researchers found that the protein starves Staph cells of zinc and manganese, essential metals that the bacterial cells need to survive and grow. But when they exposed cellular models with calprotectin to an antibiotic called cefazolin, they made a staggering finding: the antibiotic no longer killed the bacteria. Something was preventing antibiotics from doing their job.
Further research by the lab showed that when calprotectin whisks away zinc, it is also stealing a necessary metal co-factor that autolysins need to effectively degrade bacterial cell walls. They confirmed their finding in a mouse model, demonstrating that the efficacy of oxacillin was significantly enhanced in mice that do not make calprotectin.
Future Studies
The finding is yet another emerging example that antibiotic tolerance stemming from an individual's own immune system, rather than a pathogen alone. Having identified a new player in antibiotic tolerance, the Conlon lab is now investigating drug candidates that can reduce calprotectin levels and/or increase zinc levels in patients to help antibiotics better fight off infections.
"Collectively, these effects highlight an underexplored dimension of antibiotic susceptibility that could be therapeutically targeted to improve treatment outcomes in patients." said Velez.
Researchers are going to study other bacterial species that require zinc for autolytic activity, including Clostridioides difficile, Streptococcus pneumoniae, Helicobacter pylori, and Escherichia coli, to see if they, too, are developing tolerance due to calprotectin.
The presented research was 100% funded by the National Institute 375 of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers R01AI179695 and R21AI159369.
