Teicoplanin – Tigecycline Combination Shows Synergy Against Mycobacterium abscessus

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.

Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41

“…Checkerboard titration assay. This assay was carried out in 96-well microtiter plates as previously described using optical density to assess growth [24]. Eight concentrations of CLR were tested.…”

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

“…Combinations of avibactam with each of the following drugs including ampicillin, amoxicillin, tebipenem, and panipenem displayed synergistic effects against M. abscessus. Furthermore, the carbapenems, tebipenem, and panipenem also exhibited synergy with a novel boronic acid β-lactamase inhibitor, vaborbactam ( Aziz et al, 2018 ). Thus, non-β-lactam-based β-lactamase inhibitors such as avibactam and vaborbactam can potentially extend the spectrum of β-lactams employed for the treatment of largely incurable, chronic M. abscessus pulmonary infections.…”

“…For example, vancomycin, an inhibitor of cell wall synthesis, exhibited synergy with clarithromycin, an inhibitor of protein synthesis, in M. abscessus ( Mukherjee et al, 2017 ). Likewise, a combination of tigecycline (which inhibits protein synthesis) with teicoplanin (which disrupts peptidoglycan synthesis) displayed a strong synergistic effect against M. abscessus ( Aziz et al, 2018 ). Since the mycobacterial cell envelope forms a major permeability barrier, drugs that perturb cell wall integrity, are likely to synergize with drugs having intracellular targets ( Le Run et al, 2018 ).…”

Mycobacterium abscessus and β-Lactams: Emerging Insights and Potential Opportunities

“…As combination regimens are essential for clinical management of Mab infections, several studies have evaluated antibiotic synergy against Mab with mixed results (Cremades et al, 2009 ; Shen et al, 2010 ; Bastian et al, 2011 ; Choi et al, 2012 ; van Ingen et al, 2012 ; Oh et al, 2014 ; Singh et al, 2014 ; Ferro et al, 2016 ; Mukherjee et al, 2017 ; Aziz et al, 2018 ; Pryjma et al, 2018 ; Schwartz et al, 2018 ; Zhang et al, 2018 ). In vitro studies have shown variable synergy of β-lactams in combination with other drugs.…”