Scientists at St. Jude Children’s Research Hospital have found a way to use a bacterium’s own drug resistance mechanisms against itself, presenting a potentially safer and more effective way to treat certain antibiotic-resistant infections.
The researchers found that a structurally modified version of the drug florfenicol exploits drug resistance mechanisms in Mycobacterium abscessus to amplify the effect of the antibiotic perpetually.
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The approach is specific to M. abscessus and closely related bacterial species, which minimizes the host mitochondrial toxicity and microbiome disruption that often result from long-term antibiotic treatment. This type of “resistance hacking” represents a new and exciting frontier in the effort to combat antibiotic-resistant bacteria. The findings were published in Nature Microbiology.
Multidrug-resistant bacteria
M. abscessus is a species of rapidly growing multidrug-resistant bacteria that is known to infect humans. Dubbed the “antibiotic nightmare,” M. abscessus harbors a complex set of intrinsic resistance mechanisms that act as a gauntlet for antibiotics to surpass.
Long-term antibiotic treatment can lead to host mitochondrial toxicity, which is associated with hearing loss and significant healthy microbiome disruption. However, without proper treatment, M. abscessus infections quickly become life-threatening in people with obstructive lung disease and compromised immune systems, such as those with hematological malignancies.
“One of the most prominent groups at risk of M. abscessus infections is critically ill patients, like we have at St. Jude,” explained co-corresponding author Richard Lee, PhD, St. Jude Department of Chemical Biology and Therapeutics. “Since this bacterium is intrinsically resistant, treating patients with strong antibiotics for long enough just means only the most antibiotic-resistant bugs survive, which is why these infections are problematic.”
Antibiotic hijacks mycobacterial resistance tools
At the center of this resistance is the WhiB7 “resistome,” a set of antibiotic-limiting genes in M. abscessus.
“WhiB7 is a master regulator of ribosomal stress, and many antibiotics used to treat mycobacteria target the ribosome,” explained first author Gregory Phelps, PhD, formerly a graduate student in the Department of Chemical Biology and Therapeutics and currently a postdoctoral researcher in the Department of Structural Biology. “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.”
While working on the development of chloramphenicol analogs, the researchers noticed that a modified version of the antibiotic florfenicol had strong antibiotic activity against normal M. abscessus but had no effect on a strain that lacked WhiB7. “This was the opposite of what we expected, and it was repeatable,” said Phelps. “That suggested something unusual was happening.”
Further investigation revealed that the engineered florfenicol acted as a “prodrug”: a chemical that lacks activity until it converts into the active drug form within the bacterium.
Active form
The florfenicol prodrug is converted into its active form by Eis2, a protein that WhiB7 induces for drug resistance. As WhiB7 is activated, more Eis2 proteins are made, which in turn generate more of the antibiotic’s active form. The activated florfenicol analog is then able to inhibit the ribosome, subsequently activating WhiB7, creating a perpetual cascade that continuously amplifies the antibiotic’s effect.
“The exciting part of this proof-of-concept is that it shows you can use the resistance genes to actually reverse resistance,” said Lee.
A key feature of this approach is its safety profile; the prodrug’s lack of activity means it avoids much of the toxicity associated with phenicol derivatives. “Many antibiotics hit mitochondria, which leads to mitochondrial toxicity, a real problem with this class of drugs,” Lee said. “But this pathway avoids mitochondrial toxicity, giving it a much larger safety window. This is the real advantage of this approach.”
Exciting opportunity
The approach has not been explored clinically but represents an exciting new opportunity for research. Cycling the use of this antibiotic with existing antibiotics may provide the one-two knockout punch needed to tackle drug-resistant M. abscessus infections.
“Treatment of these infections takes so long. Cycling hasn’t been studied yet, but that’s the direction we are going in,” Lee said.
The team is also exploring how this approach may be used in other bacterial species with rational prodrug design to exploit resistance proteins. “We’re looking at how generalizable this strategy is,” said Phelps. “With data science and structural biology, we can begin to identify high-impact proteins in clinically relevant pathogens.”
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