Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria

Abstract

Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy.

The veterinary anti-parasitic selamectin is a novel inhibitor of the mycobacterial DprE1 enzyme

“…Protein sequence in this region of the DprE1 enzyme was highly conserved among different mycobacteria ( Figure S2 ) and shows almost no variation except for Leu275. Our finding that the moiety at the position 275 influences selamectin binding to DprE1 was consistent with the previous reports of selamectin activity against mycobacteria: M. avium , which carries a Val residue (with the smallest side chain in the series) at the 275 position is the less sensitive (MIC= 16 μg/mL); M. bovis, M. tuberculosis and M. smegmatis carry a Leu and show a medium sensitivity to selamectin (MIC= 2-4 μg/mL); M. kansasii , bearing the largest amino acid (Phe) is the most sensitive to selamectin (MIC= 0.5 μg/mL) [9,11]. M. abscessus , carrying a Leu, represents an exception with an MIC >32 μg/mL [11]; however, M. abscessus DprE1 carries an extra N-terminal 40 residues domain and shows the lowest sequence conservation ( Figure S2 ).…”

“…finding new applications for clinically approved drugs, is an alternative to the traditionally time and resource consuming drug discovery process [8]. Following this approach, the anti-parasitic family of the avermectins was found to kill M. tuberculosis and other mycobacteria, a surprising finding since they were traditionally believed to be inactive against bacteria [9][10][11]. Avermectins are a family of 16-membered macrocyclic lactones with broad spectrum anthelmintic activity initially isolated from the soil-dwelling Streptomyces avermitilis [12].…”

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs

“…Buruli ulcer is presently the third most common mycobacterial disease in humans, after TB and leprosy [38][39][40]. More recently, it was shown that avermectins are active against a variety of non-tuberculous mycobacteria of increasing relevance in pulmonary infections concomitant with cystic fibrosis [41].…”

Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication

“…In 1987, IVM was registered by Merck for the onchocerciasis (river blindness – a parasitic worm infection) in humans under the Mectizan Donation Program (MDP) with a mass treatment in 1988 [15] . As of June 2021, IVM is the only macrocyclic lactone drug approved for onchocerciasis and strongyloidiasis (a roundworm/nematode infection) in humans by the US Food and Drug Administration (FDA) [16] . This incredible discovery and deployment of IVM by Satoshi Ōmura, and William C. Campbell had won them the 2015 Nobel Prize in Physiology or Medicine [17] .…”