Differential Interactions of Rifabutin with Human and Bacterial Membranes: Implication for Its Therapeutic and Toxic Effects

Pinheiro, Marina; Arêde, Mariana; Nunes, Cláudia; Caio, João M.; Moiteiro, Cristina; Lúcio, Marlene; Reis, Salette

doi:10.1021/jm301116j

Cited by 30 publications

(38 citation statements)

References 45 publications

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“…Although the mechanism is still not well established, the cytotoxic behavior might be due in part to the lipophilic character of RFB. It presents a high membrane lipid tropism, resulting in high penetration into the cells, which can impose increased toxicity [46].…”

Section: Evaluation Of Cell Membrane Integritymentioning

confidence: 99%

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

et al. 2016

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Tuberculosis remains a major global health problem and alternative therapeutic approaches are needed. Considering the high prevalence of lung tuberculosis (80% of cases), the pulmonary delivery of antitubercular drugs in a carrier system capable of reaching the alveoli, being recognised and phagocytosed by alveolar macrophages (mycobacterium hosts), would be a significant improvement to current oral drug regimens. Locust bean gum (LBG) is a polysaccharide composed of galactose and mannose residues, which may favour specific recognition by macrophages and potentiate phagocytosis. LBG microparticles produced by spray-drying are reported herein for the first time, incorporating either isoniazid or rifabutin, first-line antitubercular drugs (association efficiencies >82%). Microparticles have adequate theoretical properties for deep lung delivery (aerodynamic diameters between 1.15 and 1.67 µm). The cytotoxic evaluation in lung epithelial cells (A549 cells) and macrophages (THP-1 cells) revealed a toxic effect from rifabutin-loaded microparticles at the highest concentrations, but we may consider that these were very high comparing with in vivo conditions. LBG microparticles further evidenced strong ability to be captured by macrophages (percentage of phagocytosis >94%). Overall, the obtained data indicated the potential of the proposed system for tuberculosis therapy.

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Section: Evaluation Of Cell Membrane Integritymentioning

confidence: 99%

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

et al. 2016

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“…To mimic the mammalian membrane 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC) was chosen as it is widely used. 22,23 To mimic the bacterial membrane, a mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) at 1:1 molar ratio was chosen as it has been described as one of the most biologically relevant model membranes for studying the S. aureus strain. 24 ■ EXPERIMENTAL SECTION Reagents.…”

Section: ■ Introductionmentioning

confidence: 99%

A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells

et al. 2015

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Antimicrobial peptides are widely recognized as an excellent alternative to conventional antibiotics. MSI-78, a highly effective and broad spectrum AMP, is one of the most promising AMPs for clinical application. In this study, we have designed shorter derivatives of MSI-78 with the aim of improving selectivity while maintaining antimicrobial activity. Shorter 17-mer derivatives were created by truncating MSI-78 at the N-and/or C-termini, while spanning MSI-78 sequence. Despite the truncations made, we found a 17-mer peptide, MSI-78(4−20) (KFLKKAKKFGKAFVKIL), which was demonstrated to be as effective as MSI-78 against the Gram-positive Staphylococcus strains tested and the Gram-negative Pseudomonas aeruginosa. This shorter derivative is more selective toward bacterial cells as it was less toxic to erythrocytes than MSI-78, representing an improved version of the lead peptide. Biophysical studies support a mechanism of action for based on the disruption of the bacterial membrane permeability barrier, which in turn leads to loss of membrane integrity and ultimately to cell death. These features point to a mechanism of action similar to the one described for the lead peptide MSI-78.

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“…[54] On the other hand, it is well known that the toxic effects of this class of drugs are strongly influenced by their affinity to biological membranes. [55] Therefore, the RFB analogs may exhibit more pronounced side effects as the discoloration of the skin, eyes, and body fluids, and further studies are needed to ensure their safety before they can reach the market. [55] In summary, we have provided a comprehensive study of the interaction of RFB and its analogs with lipids, providing useful information about the relationship between the chemical structures of the antimycobacterial compound and changes in the biophysical properties of the membrane.…”

Section: Discussionmentioning

confidence: 99%

“…[55] Therefore, the RFB analogs may exhibit more pronounced side effects as the discoloration of the skin, eyes, and body fluids, and further studies are needed to ensure their safety before they can reach the market. [55] In summary, we have provided a comprehensive study of the interaction of RFB and its analogs with lipids, providing useful information about the relationship between the chemical structures of the antimycobacterial compound and changes in the biophysical properties of the membrane. The knowledge about the structure-activity relationship of the drugs in the membranes and the lipid-drug interaction is crucial to understanding the mechanism of action at the molecular level, which is essential to develop more effective and safer antibiotics to effectively fight TB.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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This 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-α-phosphatidylcholine:cholesterol in a molar ratio of 4:1 are chosen to mimic biological membranes. Several accurate biophysical techniques are used to establish a putative relationship between the chemical structure of the antimycobacterial compounds and their activity on the membranes. A combination of in situ experimental techniques, such as Langmuir isotherms, Brewster angle microscopy, polarization-modulated infrared reflection-absorption spectroscopy, and small-angle X-ray scattering, is used to assess the drug-membrane interaction. A relationship between the effect of a drug on the organization of the membranes and their chemical structure is found and may be useful in the development of new drugs with higher efficacy and fewer toxic effects.

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Differential Interactions of Rifabutin with Human and Bacterial Membranes: Implication for Its Therapeutic and Toxic Effects

Cited by 30 publications

References 45 publications

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells

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

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