Hacking resistance mechanisms to combat antibiotic-resistant bacteria

Mycobacterium abscessus is a species of bacteria that is very difficult to treat and is known to form chronic infections in humans. Dubbed the “antibiotic nightmare,” the bacterium harbors a complex set of intrinsic resistance mechanisms that act as a gauntlet for antibiotics to surpass. Treating M. Abscessus infections requires long-term antibiotic therapy that often leads to mitochondrial toxicity and consequent hearing loss, among other toxicities, including nephrotoxicity. However, without proper treatment, infections become life-threatening for people with obstructive lung disease and compromised immune systems, such as those with hematological malignancies.

Central to intrinsic drug resistance in M. abscessus is the WhiB7 transcription factor, which is activated by antibiotic-induced ribosomal stress. Once activated, it controls over 100 proteins involved in drug resistance, creating a barrier to antibiotic action. Many antimycobacterial agents, including chloramphenicol, amikacin, and clarithromycin, are targeted by WhiB7- dependent resistance mechanisms. However, in a study published in Nature Microbiology, St. Jude scientists found a way to use these mechanisms against the bacterium.

The researchers found that a modified version of the antibiotic florfenicol had strong activity against normal M. abscessus but had no effect on a strain lacking WhiB7. Further investigations revealed the engineered florfenicol (an amphenicol derivative) acted as a “prodrug,” which is a chemical that lacks activity until it converts into its active form within the bacterium. The antibiotic is activated by Eis2, a protein that WhiB7 induces for aminoglycoside drug resistance. As WhiB7 is activated, more Eis2 proteins are produced, which then generate more of the antibiotic’s active form. The activated drug can then inhibit the ribosome, subsequently activating WhiB7, creating a perpetual cascade that amplifies the antibiotic’s effect.

“The exciting part of this proof-of-concept study is that it shows you can use the resistance genes to actually reverse resistance,” said co-corresponding author Richard Lee, PhD, Department of Chemical Biology & Therapeutics.

A key feature of this approach is its safety profile, which avoids much of the toxicity typically associated with phenicol derivatives. “Many antibiotics also inhibit mitochondria, as their ribosomes are similar, which leads to mitochondrial toxicity, a real problem with this class of drugs,” Lee said. “But our approach avoids mitochondrial toxicity, because humans lack the prodrug-activating enzyme, creating a larger safety window. This is the real advantage of this approach.”

These findings offer an exciting avenue for further research in novel mechanism-based drug discovery for M. abscessus and the pre-clinical development of the amphenicol series. Cycling the use of amphenicols with existing antibiotics may provide the clincher needed to tackle drug-resistant M. abscessus infections. The team is also exploring how this approach can be applied to other bacterial species through rational prodrug design to exploit resistance proteins.