Title : From bench to mouse: Conjugated oligoelectrolytes potentiate frontline anti-mycobacterial antibiotics against Mycobacterium abscessus
Abstract:
Mycobacterium abscessus (MAB) is one of the most drug-resistant non-tuberculous mycobacteria, with multifaceted intrinsic resistance mechanisms and poor clinical outcomes. Novel therapeutic strategies are hence urgently needed.
Conjugated oligoelectrolytes (COEs) are emerging as a promising new class of molecules that can be tailored to serve as antimicrobials. Their structures are characterized by a linear, rigid conjugated backbone and cationic pendant groups, typically quaternary ammonium moieties, attached at both ends. COEs display broad spectrum antimicrobial activities and are understood to be membrane specific agents. It is hypothesised that COEs intercalate into the membrane lipid bilayer thereby disrupting cellular membrane integrity.
Combination therapy, an increasingly vital strategy against AMR, enhances treatment efficacy, reduces resistance development, and broadens the spectrum of activity. This study examines the interactions of COE-1b with frontline antimycobacterial drugs and broad spectrum antibiotics to better understand individual and complementary mechanism(s) of action.
Synergy was first assessed against MAB ATCC 19977 by checkerboard assay and subsequently validated in a panel of MAB clinical isolates. Kill kinetics studies were performed on selected combinations and efficacy was further evaluated in biofilm, macrophage infection, and murine infection models. Transmission electron microscopy (TEM) was used to visualise envelope disruption.
It was found that COEs display strong and broad spectrum synergy with multiple antibiotic classes against MAB. Combining COE-1b with Clarithromycin gives rise to strong synergy (FIC ≤ 0.5) and bactericidal effects, which is of relevance given the inducible macrolide resistance in MAB as well as the bacteriostatic nature of macrolides. This effect was also reflected in biofilm, macrophage infection, and murine infection models. TEM imaging revealed that COE-1b disrupted the mycobacterial envelope (Figure 1). It is hence reasonable to assume that COE-1b facilitates intracellular access of Clarithromycin. Of particular interest was also the development of unique intracellular vesicle bodies and intracellular lipid inclusions, the purpose of which warrants further investigations.
In conclusion, COEs can be strategically combined with an antibiotic to optimise antibacterial activities against MAB. The robust synergy between COE-1b and Clarithromycin, with activity confirmed across different clinically relevant infection models, highlights the translational potential of the COE molecule as part of future treatment regiments.
