Mycobacterium abscessus lurks in patients with chronic lung diseases, amplifying symptoms such as persistent cough and build-up of thick, dark sputum. In patients with cystic fibrosis, these bacteria can impair lung function over time, sometimes even necessitating a transplant. But patients are ineligible for transplant until the infection is cleared, which has been nearly impossible (1).

Recently, Mary Jackson, a microbiologist from Colorado State University, and her team reported that some antimalarial drugs are active against M. abscessus infections in mice with chronic lung disease. The compounds could improve the quality of life for patients with limited treatment options (2). 

“We thought okay, let’s try to figure out what is important for the bacterium to cause disease and what is important for this bacterium to allow it to proceed to chronic infections and develop drug tolerance,” said Jackson. “If we can understand how this bacterium does this, we can target this particular process with a drug so that we restore antibiotic susceptibility and try to clear it more efficiently.”    

Jackson looked to M. abscessus’ distant cousin M. tuberculosis for clues. M. abscessus causes lesions like those found in patients infected with M. tuberculosis, and it carries a regulatory system, DosRS, that is similar to DosRST, which enables M. tuberculosis to dodge the effects of antibiotics by entering a dormant state (3). Jackson and her team decided to investigate whether this system provides a similar antibiotic dodging effect in M. abscessus. Her team thwarted the bacteria’s ability to form large, sticky biofilms — fortresses that shield them from antibiotics — in immunodeficient mice infected with M. abscessus by knocking out genes critical to DosRS function. Knocking out these genes also decreased the bacteria’s drug tolerance.

The research team then worked with collaborators at Michigan State University and the University of Nebraska Medical Center to find therapeutics that target the DosRS system. Some antimalarial drugs actually target some of the proteins found in the DosRST system in M. tuberculosis (3), so the team decided to test the naturally occurring antimalarial drug artemisinin and two synthetic derivatives, OZ277 and OZ439, in immunodeficient mice both acutely and chronically infected with M. abscessus.

The drugs didn’t slow bacterial replication any more than antibiotics commonly used it the clinic. But when using the antimalarials in combination with antibiotics that the bacteria were normally able to avoid, it amplified the effects of the antibiotic and further reduced bacterial replication.

Petros Karakousis, an M. tuberculosis researcher at Johns Hopkins University School of Medicine who was not involved in this study, said that the results are promising, but he isn’t sure if they will hold true for humans.

“The reality is that there aren't any great models, animal models, and this is really what's held back the field, especially for these non-tuberculous mycobacteria [like M. abscessus],” said Karakousis. “The problem is that the bacteria get cleared spontaneously [in mice]. So really, what they have to do then is to give something like corticosteroids that compromise the immune system to allow the bacteria to multiply.”  

Jackson acknowledges the limitations of the immunodeficient mouse model her team used. In the future, they hope to find a model that better reflects the pathology of M. abscessus infections to study the possible interactions with other pathways within the bacterium. 

Jackson is already working on testing the drug in the most relevant model of all: humans.  OZ439 is in phase IIb clinical trials and is considered safe in adults and pediatric patients.  The researchers are now moving towards small compassionate use trials for patients suffering with persistent M. abscessus infections.  

“We would like to see if this shows any efficacy in this patient [population]. If it does, then it would be really good news,” said Mary Jackson. 

References

1. Degiacomi, G. et al. Mycobacterium abscessus, an Emerging and Worrisome Pathogen among Cystic Fibrosis Patients. Int J Mol Sci  20, 5868 (2019).
2. Belardinelli, J. M. et al. Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in. Sci Transl Med  14, eabj3860 (2022).
3. Zheng, H. et al., Inhibitors of Mycobacterium tuberculosis dosrst signaling and persistence. Nat Chem Biol  13, 218-467 (2017).