Abstract
Lung disease caused by non-tuberculous mycobacteria (NTM), relatives of Mycobacterium tuberculosis, is increasing. M. abscessus is the most prevalent rapid growing NTM. This environmental pathogen is intrinsically resistant to most commonly used antibiotics, including anti-tuberculosis drugs. Current therapies take years to achieve cure, if cure if achieved. Thus, there is an urgent medical need to identify new, more efficacious treatments. Here, we explore the possibility of repurposing antibiotics developed for other indications. We asked whether novel two-drug combinations of clinically used antibiotics can be identified that show synergistic activity against this mycobacterium. An in vitro checkerboard titration assay was employed to test 180 dual combinations of 41 drugs against the clinical isolate M. abscessus Bamboo. The most attractive novel combination was further profiled against reference strains representing three sub-species (M. abscessus subsp. abscessus, massiliense and bolletii) and a collection of clinical isolates. This resulted in the identification of a novel synergistic antibiotic pair active against the M. abscessus complex: the glycopeptide teicoplanin with the glycylcycline tigecycline showed inhibitory activity at 2–3 μM (teicoplanin) and 1–2 μM (tigecycline). This novel combination can now be tested in M. abscessus animal models of infection and/or patients.
Highlights
Among the rapid growing non-tuberculous mycobacteria (NTM), M. abscessus is the most common cause of lung disease (Griffith et al, 2007; Medjahed et al, 2010; Hoefsloot et al, 2013)
Teicoplanin was obtained from Sigma-Aldrich, while tigecycline was obtained from Adooq BioScience
For the checkerboard titration assay determination of the activity of the teicoplanin + tigecycline hit against the various M. abscessus subspecies within the M. abscessus complex, M. abscessus subsp. abscessus (ATCC 19977), M. abscessus subsp. bolletii (CCUG 50184-T) and M. abscessus subsp. massiliense (CCUG 48898-T) were used
Summary
Among the rapid growing non-tuberculous mycobacteria (NTM), M. abscessus is the most common cause of lung disease (Griffith et al, 2007; Medjahed et al, 2010; Hoefsloot et al, 2013). A poor rate of successful chemotherapeutic treatment makes M. abscessus disease a chronic incurable infection (Griffith et al, 2007). M. abscessus infections are treated by a multi-drug regimen consisting of a macrolide (clarithromycin), amikacin and either cefoxitin or imipenem (Benwill and Wallace, 2014; Ryu et al, 2016). The treatment issues are further complicated by the ability of two out of three sub-species of M. abscessus to develop macrolide resistance upon exposure to subinhibitory concentrations of the drug (Nash et al, 2009; Bastian et al, 2011; Maurer et al, 2014)
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