Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria.

Lara Muñoz-Muñoz,Carolyn Shoen,Tim J Bull,Michael Cynamon,Asunción Vitoria,Gaye Sweet,Santiago Ramón-García,Charles J Thompson

doi:10.3390/antibiotics10040381

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.

Highlights

Pulmonary nontuberculous mycobacteria (NTM) infections are typically caused by Mycobacterium avium-intracellulare complex (MAC), Mycobacterium kansasii, and M. abscessus complex (MABSC) [11,12]
Thought to be inactive against bacteria, we previously identified the bactericidal activity of macrocyclic lactones (ML) against certain mycobacterial species, including Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium smegmatis, M. ulcerans and M. marinum, [26,27]
Eight ML were tested against a panel of 80 NTM, including reference strains and clinical isolates from local hospitals (Figure 1, Table S1)

Summary

Introduction

The incidence of documented infections caused by nontuberculous mycobacteria (NTM) are on the rise worldwide and becoming a new neglected global health concern [1,2,3]. Reasons for this include NTM outbreaks in cosmetic and surgical procedures, potential transmission of Mycobacteroides abscessus among patients with cystic fibrosis (CF), and the increasing number of vulnerable individuals at risk of developing these infections, i.e., immunocompromised patients or patients with chronic pulmonary pathologies [4,5,6]. Most common diseases caused by NTM are pulmonary, disseminated, or skin and soft tissues infections [9,10]. Skin and soft tissue infections are often associated with trauma, surgical procedures, or contaminated medical equipment with

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