St. Jude Children’s Research Hospital researchers have taken an innovative new tack to combat infections. This approach takes direct aim at the fast-spreading and superbug Mycobacterium abscessus. This invasive species poses immense public health threats. It particularly puts at risk people with obstructive lung disease or immunodeficiency, such as those in the fight against hematological malignancies.
Unfortunately, M. abscessus is recognized for its complicated and poorly understood array of intrinsic resistance mechanisms that prevent antibiotics from working. At the heart of this resistance is WhiB7, a master regulator that controls more than 100 proteins involved in antimicrobial resistance. As antibiotics chloramphenicol and clarithromycin induce whiB7, this bootstraps it into an even more impenetrable rampart against successful therapeutic onslaughts.
The St. Jude research team understood this predicament. Instead, they wanted to find a way to turn M. abscessus’s own resistance mechanisms on the bacteria. Their work transformed the human antibiotic florfenicol into florfenicol amine, which showed potent activity against M. abscessus. The drug’s unique activation by the bacterium’s own built-in resistance—in particular, via an aminoglycoside-modifying enzyme known as Eis2.
Scientists are betting that rotating the use of florfenicol amine with current antibiotics could pack a one-two punch. We show this strategy effectively targets drug-resistant M. abscessus infections specifically. Gregory Phelps, Ph.D., emphasized the significance of WhiB7 in this context:
“Anytime you use antibiotics such as chloramphenicol or clarithromycin, WhiB7 is activated and controls over 100 proteins involved in antimicrobial resistance. It’s a barrier for effective therapeutics.”
Dr. Richard Lee noted that critically ill patients at St. Jude are among the most vulnerable to M. abscessus infections:
“One of the most prominent groups at risk of M. abscessus infections is critically ill patients, like we have at St. Jude.”
This new strategy aims explicitly at M. abscessus and closely related bacterial species. In so doing, it greatly reduces the chances of mitochondrial toxicity and microbiome disruption, both of which are hallmarks of many popular, pre designated antibiotics.
Researchers are currently investigating how generalizable this innovative strategy may be for combating antibiotic resistance beyond M. abscessus:
“Many antibiotics hit mitochondria, which leads to mitochondrial toxicity, a real problem with this class of drugs. But this pathway avoids mitochondrial toxicity, giving it a much larger safety window. This is the real advantage of this approach.”
With the care required for complex M. abscessus infections frequently consisting of long-term therapy, new approaches are key to bringing effective options and interventions to these patients. Dr. Lee mentioned that while cycling hasn’t been extensively studied yet, it represents a promising direction for future research:
“We’re looking at how generalizable this strategy is,” stated Dr. Phelps.
This proof-of-concept study highlights an unexpected breakthrough, where scientists found they could leverage resistance genes to potentially reverse antibiotic resistance:
“Treatment of these infections takes so long. Cycling hasn’t been studied yet, but that’s the direction we are going in.”
This proof-of-concept study highlights an unexpected breakthrough, where scientists found they could leverage resistance genes to potentially reverse antibiotic resistance:
“The exciting part of this proof-of-concept is that it shows you can use the resistance genes to actually reverse resistance,” Dr. Lee remarked.