The antimicrobial compound K21, used in dental products, extended roundworm lifespan through the same process that helps human immune cells kill bacteria

The antimicrobial compound K21, used in dental products, extended roundworm lifespan through the same process that helps human immune cells kill bacteria

An international research team showed that K21, an antimicrobial compound already used in dentistry, helps human macrophages kill bacteria more effectively by promoting the controlled recycling of mitochondria, a process called mitophagy. The same process produced a statistically significant increase in lifespan in the roundworm Caenorhabditis elegans.

K21 is a synthetic antimicrobial compound sold under the FiteBac brand. It has been used in FDA-approved dental products for more than ten years and has been tested as a treatment for non-healing burn wounds and diabetic wounds. It inhibits a broad range of bacteria, viruses, and fungi without disrupting their membranes and is not toxic to human cells. Its ability to support wound healing led the authors to hypothesize that K21 might act through macrophages, immune cells that kill bacteria and coordinate wound healing. To test this, they treated human macrophages with K21 and infected them with Enterococcus faecalis, a bacterium that can survive inside cells and causes hospital-acquired infections. Macrophage activation changed little, but almost no viable bacterial colonies grew from infected cells treated with K21. The bacteria entered the cells just as readily, but could no longer survive inside them. The results were published on September 17 in Life Science Alliance.

Single-cell RNA sequencing provided an explanation. In macrophages, K21 triggered the division and subsequent recycling of mitochondria, the structures that supply cells with energy. This recycling process is called mitophagy. Several independent methods confirmed increased activity of DRP-1, a protein that initiates mitochondrial division. Two known triggers of mitophagy are oxygen deprivation and damage to the mitochondrial membrane. K21 bypassed both danger signals by stabilizing DRP-1 directly. The authors describe this response as mitohormesis, a controlled metabolic stress that conditions the cell and increases its resilience. The same process can also work in the opposite direction: in smokers, SIRT3 dysfunction in alveolar macrophages damages their mitochondria and suppresses bacterial uptake.

To test the finding beyond cell culture, the researchers repeated the experiment in the roundworm Caenorhabditis elegans. Research using this organism has twice received a Nobel Prize: in 2002 for discovering the regulation of programmed cell death and in 2006 for RNA interference. Worms fed bacteria supplemented with K21 showed the same mitochondrial division and mitophagy in their intestines and lived significantly longer than controls (p<0.0001). Food intake, development, body size, and egg production remained unchanged, indicating that the effect was not due to starvation. Previous work had linked lifespan extension through mitophagy in C. elegans to atfs-1, a gene that switches on an emergency mitochondrial repair response during starvation or oxygen deprivation. K21 extended lifespan just as effectively in worms lacking this gene, indicating that it acts through a different pathway that does not depend on this emergency response. The final evidence came from matching gene responses: eight genes were switched on or off in the same direction in both human cells and worms, providing direct molecular evidence of a shared mechanism in two distantly related species.

“Roundworms and humans diverged almost a billion years ago, and the fact that the effects of K21 are reproduced so broadly in both species points to a deeply conserved target whose role extends beyond immune cells,” the authors write.

Stronger immune defense in human cells and longer lifespan in worms resulted from the same intervention in mitochondrial quality control. This provides an example of how protection against infection and longevity can depend on a shared cellular target. The authors measured lifespan extension in worms; their human experiments measured only enhanced antimicrobial defense in macrophages. Both project leaders received grants from FiteBac, the company that sells K21. K21 remains primarily a topical antimicrobial agent, with mitophagy and lifespan extension in worms representing newly identified effects.