Antituberculosis Drug Interactions with Membranes: A Biophysical Approach Applied to Bedaquiline.

Marina Pinheiro,Salette Reis,Heinz Amenitsch

doi:10.3390/membranes9110141

Marina Pinheiro, Salette Reis + Show 1 more

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https://doi.org/10.3390/membranes9110141

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Abstract

This work focuses on the interaction of the novel and representative antituberculosis (anti-TB) drug bedaquiline (BDQ) with different membrane models of eukaryotic and prokaryotic cells. The effect of BDQ on eukaryotic cell membrane models was assessed using liposomes, namely, multilamellar vesicles (MLVs) made of 1,2-dimyristoyl-rac-glycero-3-phosphocholine (DMPC) and also a mixture of DMPC and cholesterol (CHOL) (8:2 molar ratio). To mimic the prokaryotic cell membrane, 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG) and 1,1′2,2′-tetra-oleoyl-cardiolipin (TOCL) were chosen. Powerful biophysical techniques were employed, including small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS), to understand the effect of BDQ on the nanostructure of the membrane models. The results showed that BDQ demonstrated a pronounced disordering effect in the bacterial cell membrane models, especially in the membrane model with cardiolipin (CL), while the human cell membrane model with large fractions of neutral phospholipids remained less affected. The membrane models and techniques provide detailed information about different aspects of the drug–membrane interaction, thus offering valuable information to better understand the effect of BDQ on their target membrane-associated enzyme as well as its side effects on the cardiovascular system.

Highlights

Tuberculosis (TB) is a major global health concern, with the disease being the leading cause of death worldwide among infectious diseases [1]
The lipids DMPC, CHOL, DMPG, and TOCL were purchased from Avanti Polar Lipids®, (Alabaster, AL, USA)
The repeat distance d deduced from the small-angle X-ray scattering (SAXS) patterns as well as the distances between the polar head groups of DMPC obtained by wide-angle X-ray scattering (WAXS) measurements, including the correlation between the bilayers (ξ) of DMPC in the absence and in the presence of BDQ, are listed in

Summary

Introduction

Tuberculosis (TB) is a major global health concern, with the disease being the leading cause of death worldwide among infectious diseases [1]. Significant progress has been made to reduce the global impact of TB, including drug discovery (WHO, 2019). Bedaquiline (BDQ), a new drug that is known as TMC207 (Figure 1), is a diarylquinoline compound that inhibits the bacterial ATP synthase located in the inner membrane [3]. BDQ has been associated with several adverse effects, including heart failure, which has raised concerns that its risks may outweigh its benefits [4]. Because BDQ must be deeply immersed in the membrane to reach its pharmacological target, we applied a biophysical approach to study the drug with the hypothesis that some of its adverse effects, especially the cardiovascular effects may be membrane-mediated. It is well known that the efficacy of antibiotics depends on Membranes 2019, 9, 141; doi:10.3390/membranes9110141 www.mdpi.com/journal/membranes

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