Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: A biophysical approach to disease

Abstract

This work focuses on the interaction of mycolic acids (MAs) and two antimycobacterial compounds (Rifabutin and N'-acetyl-Rifabutin) at the pulmonary membrane level to convey a biophysical perspective of their role in disease. For this purpose, accurate biophysical techniques (Langmuir isotherms, Brewster angle microscopy, and polarization-modulation infrared reflection spectroscopy) and lipid model systems were used to mimic biomembranes: MAs mimic bacterial lipids of the Mycobacterium tuberculosis (MTb) membrane, whereas Curosurf® was used as the human pulmonary surfactant (PS) membrane model. The results obtained show that high quantities of MAs are responsible for significant changes on PS biophysical properties. At the dynamic inspiratory surface tension, high amounts of MAs decrease the order of the lipid monolayer, which appears to be a concentration dependent effect. These results suggest that the amount of MAs might play a critical role in the initial access of the bacteria to their targets. Both molecules also interact with the PS monolayer at the dynamic inspiratory surface. However, in the presence of higher amounts of MAs, both compounds improve the phospholipid packing and, therefore, the order of the lipid surfactant monolayer. In summary, this work discloses the putative protective effects of antimycobacterial compounds against the MAs induced biophysical impairment of PS lipid monolayers. These protective effects are most of the times overlooked, but can constitute an additional therapeutic value in the treatment of pulmonary tuberculosis (Tb) and may provide significant insights for the design of new and more efficient anti-Tb drugs based on their behavior as membrane ordering agents.

Evaluation of the Structure–Activity Relationship of Rifabutin and Analogs: A Drug–Membrane Study

“…Moreover, EPC comprises a mixture of zwitterionic phospholipids with the phosphatidylcholine head group but different saturated and unsaturated acyl chains, mostly 16:0 (sn1) and 18:1 or 18:2 (sn2). [14,15] Besides phospholipids, CHOL is also a major component of the human cell membrane, [9] and is fundamental not only to maintaining cell membrane structures, [10,11] such as lipid rafts, [12] but also to the physiology and function of the membrane. [16] Furthermore, CHOL has the ability to modulate the fluidity of the membranes and consequently their permeability.…”

“…[9][10][11] In this regard, a systematic comparison of the degree of penetration of RFB and two recently synthesized anThis work focuses on the influence of rifabutin and two novel analogs, namely, N'-acetyl-rifabutin and N'-butanoyl-rifabutin, on the biophysical properties of lipid membranes. Monolayers and multilamellar vesicles composed of egg l-a-phosphatidylcholine:cholesterol in a molar ratio of 4:1 are chosen to mimic biological membranes.…”

Interactions of bioactive molecules & nanomaterials with Langmuir monolayers as cell membrane models

“…Reproduced with permission from reference [171].Further progress has been made in this area by broadening the spectrum of interacting elements in the biological environment of lungs. A study was made regarding the influence of rifabutin and its N`-acetyl derivative as well mycotic acids, mimicking the mycobacterial membrane, on lung surfactant extract from natural porcine (Curosurf ®), taken as a model of human pulmonary surfactant[172]. When in large amounts, mycotic acids affect the pulmonary surfactant by decreasing the order of acyl chains, as indicated by PM-IRRAS measurements.This effect was concentration-dependent, and therefore the amount of mycotic acids may be critical for microorganisms to access their targets.…”

Physical-Chemical Studies of the Effect of Antibiotic Incorporation in the Structure and Molecular Organization of Clinical-Grade Lung Surfactant Monolayers and Membrane Models at the Air-Water Interface

“…Hence, before attempts are made to employ the lung surfactant with a specific drug in in vivo tests, it makes sense to verify whether the surfactant will remain stable upon interacting with the drug. Such a study can be made with Langmuir monolayers representing the lung surfactant (BANASCHEWSKI et al, 2015;BENSIKADDOUR et al, 2008b;BERQUAND et al, 2005;BANERJEE, 2005a, 2005b, 2005c, PINHEIRO et al, 2013a, 2013b, which allows for determining the molecularlevel interactions between the surfactant constituents and the drug. and fluidize the DPPC film.…”

“…Neutron reflectometry (NR) is a powerful technique to examine the structure of amphiphiles normal to the interface and provides valuable contrast variation measurements for the structural description and characterization of mixed systems such as lipid membrane models(DI COLA; GRILLO; RISTORI, 2016; KISELEV, 2011). Indeed, DPPC is a phospholipid widely used to mimic the interfacial properties of lung surfactant (LS) at the air-water interface because it is the main LS constituent (BENSIKADDOUR et al, 2008a;DUAN et al, 2013;FOLLOWS et al, 2007;FULLAGAR;HOLT;GENTLE, 2008;PINHEIRO et al, 2013a), thus it can reveal key information related to interactions with target molecules. For example, Fullagar et al applied NR on surfactant protein B…”