(566) Repurposing antimalarials drugs for the treatment of NTM infections

Background: Rapidly-growing NTM of the M. abscessus complex (MABSC), and slowly-growing NTM of the Mycobacterium avium complex (MAC) have emerged as important human pathogens globally, causing an increasing number of pulmonary infections among patients with cystic fibrosis (CF) [1]. Treatment options for MABSC and MAC pulmonary infections are few and involve lengthy combination regimens of 12-24 months with combinations of intravenous and oral antibiotics that lack cidal activity and are associated with significant toxicity. This highlights the need for alternative approaches to treat NTM infections which led to our interest in antimalarial drugs targeting the two-component regulator DosRS [2].

Methods: We deleted dosRS from M. abscessus and studied its effect in the adaptation of M. abscessus to hypoxia, bacterial survival after oxygen depletion, tolerance to a number of antibiotics in vitro and in vivo, and biofilm formation.
Then we determined if antimalarial compounds were able to inhibit DosRS signaling and recapitulated the effects of genetically disrupting DosRS in M. abscessus in vitro and in vivo.
Finally, we tested the therapeutic efficacy and adjunct therapeutic efficacy of one of this compounds in acutely and chronically MABSC-infected SCID mice.

Results: We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation.
Furthermore, we determined that three antimalarial drugs or drug candidates, artemisinin, OZ277 and OZ439, can target DosS-mediated signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity f antibiotics used in combination (Figure1).

Conclusions: We identified orally available antimalarial drugs with the potential to improve MABSC treatment both as a stand-alone therapy and when used in combination with standard-of-care antibiotics. The repurposing of these agents provides a much-needed opportunity for innovative combination chemotherapy that could be available in the foreseeable future for patients suffering from MABSC infections.

Acknowledgements: This work was supported by a research grant from the Cystic Fibrosis Foundation and NIH/National Institute of Allergy and Infectious Diseases grants AI147326, 1 S10 RR023735 (Zeiss LSM 510 Laser Scanning Microscope), and 1 S10 OD025127 (Keyence fluorescence microscope; CSU Microscope Imaging Network). J.M.B. is the recipient of a Vertex Research Innovation Award. C.A. is supported by the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant no. 845479.

References: [1] Floto, R. A.; Haworth, C. S., The growing threat of nontuberculous mycobacteria in CF. J Cyst Fibros 2015, 14 (1), 1-2.
[2] Voskuil, M. I.; Schnappinger, D.; Visconti, K. C.; Harrell, M. I.; Dolganov, G. M.; Sherman, D. R.; Schoolnik, G. K., Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 2003, 198 (5), 705-13.