The long-term objective of this research is the development of rational methods for the design and improvement of membrane-penetrating, amphipathic peptides that are antibiotic or cytolytic, or can carry other drug molecules as cargo into cells. Critical knowledge in reaching this objective is the determination of the mechanism of membrane penetration by these peptides. Peptides in this class are known to exhibit considerable target specificity, which appears to derive from the interaction of the peptides with the lipid bilayer of the target cell membrane without the intervention of protein receptors. Furthermore, the development of resistance by bacteria is much more difficult because it entails massive changes in the bacterial membranes. ? ? Three fundamental hypotheses relating to the mechanism of these peptides will be tested. The prediction is that specific features of the peptide sequences are necessary for peptides to penetrate cells or disrupt the membrane. Four naturally-occurring peptides were selected as the basis for new sequences that will be used to test the hypotheses. If correct, a powerful predictive program will be available to design peptides that function with a desired mechanism. Thus, the aim is to design peptides for cargo-delivery into cells or for cytolytic functions. Cargo-carrying peptides can be used to transport drugs into eukaryotic cells or antibiotics into bacterial cells. Surmounting cellular barriers, including intracellular compartments, is a major difficulty in the use of antibiotics. Furthermore, as bacteria increasingly develop resistance against conventional antibiotics, understanding the physical properties necessary for the rational design of new antibiotics that are not prone to resistance development is of the utmost importance. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
Project #
Application #
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Wilmington
Schools of Arts and Sciences
United States
Zip Code
Kreutzberger, Mark A; Pokorny, Antje; Almeida, Paulo F (2017) Daptomycin-Phosphatidylglycerol Domains in Lipid Membranes. Langmuir 33:13669-13679
King, Mariah J; Bennett, Ashley L; Almeida, Paulo F et al. (2016) Coarse-grained simulations of hemolytic peptide ?-lysin interacting with a POPC bilayer. Biochim Biophys Acta 1858:3182-3194
Ablan, Francis D O; Spaller, B Logan; Abdo, Kaitlyn I et al. (2016) Charge Distribution Fine-Tunes the Translocation of ?-Helical Amphipathic Peptides across Membranes. Biophys J 111:1738-1749
Kreutzberger, Mark A; Tejada, Emmanuel; Wang, Ying et al. (2015) GUVs melt like LUVs: the large heat capacity of MLVs is not due to large size or small curvature. Biophys J 108:2619-22
Cherry, Melissa A; Higgins, Sarah K; Melroy, Hilary et al. (2014) Peptides with the same composition, hydrophobicity, and hydrophobic moment bind to phospholipid bilayers with different affinities. J Phys Chem B 118:12462-70
Almeida, Paulo F (2014) Membrane-active peptides: binding, translocation, and flux in lipid vesicles. Biochim Biophys Acta 1838:2216-27
Wheaten, Sterling A; Lakshmanan, Aruna; Almeida, Paulo F (2013) Statistical analysis of peptide-induced graded and all-or-none fluxes in giant vesicles. Biophys J 105:432-43
Wheaten, Sterling A; Ablan, Francis D O; Spaller, B Logan et al. (2013) Translocation of cationic amphipathic peptides across the membranes of pure phospholipid giant vesicles. J Am Chem Soc 135:16517-25
Spaller, B Logan; Trieu, Julie M; Almeida, Paulo F (2013) Hemolytic activity of membrane-active peptides correlates with the thermodynamics of binding to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers. J Membr Biol 246:257-62
Almeida, Paulo F; Ladokhin, Alexey S; White, Stephen H (2012) Hydrogen-bond energetics drive helix formation in membrane interfaces. Biochim Biophys Acta 1818:178-82

Showing the most recent 10 out of 29 publications