While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of 1H–15N dipolar couplings and 15N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound α-helical peptides. The tilt of the helical axis, τ, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, ρ, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their τ angles (<10°) and significant difference in their ρ angles (∼25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt ρ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger ρ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal α-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted α-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ∼1.2–3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains.

§ Drs. Murphy and Parikh contributed equally and are co-senior authors Author contributions: Dr. Singal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design (Singal and Parikh); Acquisition, analysis and interpretation of the data (all authors); Drafting of the manuscript (Singal); Critical revision of the manuscript for important intellectual content (all authors); Obtained funding (Singal, Parikh); Administrative, technical, and material support (Singal and Parikh); Study supervision (Singal) Conflicts of Interest: Amit Singal was on speakers bureau for Gilead, Bayer, and Bristol Meyers Squibb. He has served on advisory boards for Gilead, Abbvie, Bayer, Eisai, Wako Diagnostics, Roche, and Exact Sciences. He serves as a consultant to Bayer, Eisai, Roche, and Glycotest. He has received research funding from Gilead and Abbvie. Neil Mehta has received research funding from Wako Diagnostics. Anjana Pillai serves as a consultant and is on speakers bureau for Eisai and BTG. Jordan Feld has received research support from Gilead, Abbvie, Merck, and Janssen. Binu John has served on advisory boards for Eisai. Catherine Frenette is on speakers bureaus for Bayer, Bristol Meyers Squibb, Gilead, Merck, Abbvie, and Eisai. She served on advisory boards for Gilead, Eisai, and Wako. She served as a consultant for Bayer and Gilead. She received research funding from Bayer. Parvez Mantry is on speakers bureaus and served on advisory boards for Gilead, Abbvie, Bayer, BMS, Eisai, Merck, and BTG. He has received research funding from Gilead and Sirtex. Michael Leise has received research funding from Abbvie. Kalyan Ram Bhamidimarri serves as scientific advisory board member for Gilead, Merck, and Abbvie. He has received research funding from Gilead. Laura Kulik is on speakers bureau for Eisai, Gilead, and Dova. She serves as an advisory board member for BMS, Eisai, Bayer, Exelixis Reena Salgia is on speakers bureau for Bayer. She has served on advisory boards for Bayer, Eisai, and Exelixis. Sanjaya Satapathy has received research support from Gilead and Bayer.He has served on advisory boards or as a consultant for Abbvie and Gilead.

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http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/12-6-reading-dao a video presentation of this article

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BACKGROUND Capecitabine is considered a first line agent in adjuvant therapy for breast and colorectal cancer. However, cases of severe diarrhea have been reported with increasing frequency in recent years. When diarrhea is severe and prolonged, capecitabine associated ileitis should be considered as a possible etiology. CASE SUMMARY Herein, we present two cases of capecitabine ileitis, specifically involving the terminal ileum and ascending colon. We will demonstrate the disease course and treatment modalities applied to alleviate this condition, as well as discuss the merits of using colonoscopy to aid in diagnosis. CONCLUSION Ultimately our cases demonstrate that symptomatic management with traditional anti-diarrheal medications is largely ineffective. Prompt recognition and discontinuation of capecitabine is an imperative step in proper management of this condition and colonoscopy with biopsy can be helpful when the diagnosis is unclear.

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The antimicrobial peptides (AMPs) PGLa and magainin 2 (MAG2) found in the skin of the African frog Xenopus laevis show a synergistic enhancement of their activity [1]. Both peptides form amphipathic a-helices when binding to a lipid membrane, and their orientation in membranes have been determined with high accuracy using solid state 2 H-, 15 N-, and 19 F-NMR. We have previously shown that PGLa inserts into DMPC/DMPG bilayers in the presence of an equimolar amount of MAG2, but not on its own, even at high concentrations [2]. This indicates formation of stable heterodimeric peptide pores, which in turn can explain the synergism between the peptides. Here, we show that MAG2, both with and without PGLa, always stays almost flat on the membrane surface; however, there is a small change in the orientation in the presence of PGLa, and dynamics is reduced, indicating that a PGLa-MAG2 complex is formed. In POPC/POPG, both peptides stay flat on the membrane surface, alone or combined. This is in agreement with our previous finding that the AMP MSI-103 always stays flat on the surface in unsaturated lipids (or more generally in lipid systems with negative spontaneous curvature), but can insert deeper into the membrane in saturated lipids (where the spontaneous curvature is positive) [3].