Molecular Interaction of Rifabutin on Model Lung Surfactant Monolayers

Abstract

Tuberculosis is one of the most relevant problems for global health care. The design of new drugs against tuberculosis is aimed at maximizing impact against the disease, as well as minimizing the toxicological effect on the lung surfactant. In this work, the antituberculosis drug Rifabutin is studied in combination with phospholipid Langmuir monolayers as models of the lung surfactant monolayer. The zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and the anionic 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) were used as model phospholipids. A combination of in situ experimental techniques of Brewster angle microscopy, polarization-modulated infrared reflection-absorption spectroscopy, and UV-vis reflection spectroscopy with computer simulations has been used. The interactions between Rifabutin and the DPPC and DPPG Langmuir monolayers were described as the formation of an inclusion complex. The phospholipid-Rifabutin inclusion complex prevents the penetration of the Rifabutin into the alkyl chain region of the phospholipids, leading to a disruption of the monolayer structure and a possible toxicological effect.

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

“…Moreover, the brighter regions observed are due to the presence of antimycobacterial molecules at the air/solution interface, recognizable in the form of relatively thick local aggregates with a high refractive index, as previously described. [10] Additionally, these bright spots emerging for pressures above 0 mNm À1 are in an localized pattern and appear to be associated with larger islands, which result from the phase separation ( Figure 3, marked with arrows). Thus, the segregation of the monolayer takes place in the presence of the antimycobacterial compounds, which suggest that RFB and its analogs are responsible for changes in the molecular packing of the lipid mixture at the air/solution interface.…”

“…[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.…”

“…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.…”

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

“…The antituberculars rifabutin [170] and its N`-acetyl derivative [171] were studied in model lung surfactants (DPPC:DPPG = 9:1). Films from both phospholipids significantly expanded on rifabutin-containing subphase, indicating insertion of drug molecules into the monolayers, as confirmed with UV-vis studies.…”

Vibrational spectroscopy for probing molecular-level interactions in organic films mimicking biointerfaces

“…Because DPPC and DPPG are the most abundant lipid components in the inner interface of the lungs, they have been widely used in interaction studies [127], for which spectroscopic methods are ideally suited. Flach et al [128] isolated a specific pulmonary protein from lung porcine to investigate, via IRRAS, the role of the two thioester-linked palmitoyl chains located near the N-terminus from deacylated protein SP-C. Deacylation of SP-C produced more fluid DPPC monolayers, with the helical-secondary structure and tilt-angle of the protein remaining essentially unchanged.…”