Designing and identifying ß-hairpin peptide macrocycles with antibiotic potential.

Peptide macrocycles are a rapidly emerging class of therapeutic, yet the design of their structure and activity remains challenging. This is especially true for those with ß-hairpin structure due to weak folding properties and a propensity for aggregation. Here, we use proteomic analysis and common antimicrobial features to design a large peptide library with macrocyclic ß-hairpin structure. Using an activity-driven high-throughput screen, we identify dozens of peptides killing bacteria through selective membrane disruption and analyze their biochemical features via machine learning. Active peptides contain a unique constrained structure and are highly enriched for cationic charge with arginine in their turn region. Our results provide a synthetic strategy for structured macrocyclic peptide design and discovery while also elucidating characteristics important for ß-hairpin antimicrobial peptide activity.

Synthetic antibacterial discovery of symbah-1, a macrocyclic ß-hairpin peptide antibiotic.

The rapid development and spread of antibiotic resistance necessitate the development of novel strategies for antibiotic discovery. Symbah-1, a synthetic peptide antibiotic, was identified in a high-throughput antibacterial screen of random peptide sequences. Symbah-1 functions through membrane disruption and contains broad spectrum bactericidal activity against several drug-resistant pathogens. Circular dichroism and high-resolution mass spectrometry indicate symbah-1 has a ß-hairpin structure induced by lipopolysaccharide and is cyclized via an intramolecular disulfide bond. Together these data classify symbah-1 as an uncommon synthetic member of the ß-hairpin antimicrobial peptide class. Symbah-1 displays low hemolysis but loses activity in human serum. Characterization of a symbah-1 peptide library identified two variants with increased serum activity and protease resistance. The method of discovery and subsequent characterization of symbah-1 suggests large synthetic peptide libraries bias toward macrocyclic ß-hairpin structure could be designed and screened to rapidly expand and better understand this rare peptide antibiotic class.

Comparison of occupational radiation exposure from myocardial perfusion imaging with Rb-82 PET and Tc-99m SPECT.

OBJECTIVE: Rubidium-82 (Rb-82) PET myocardial perfusion imaging (MPI) has superior diagnostic accuracy, at least similar prognostic value, and lower patient radiation exposure when compared with technetium-99m single-photon emission computed tomography (Tc-99m SPECT) MPI. The aim of this study was to compare occupational radiation exposure from the two modalities and show that improvements for the patient do not come at a cost to staff. MATERIALS AND METHODS: Electronic personal dosimeters were worn by staff involved in the administration and imaging of routine clinical Tc-99m SPECT and Rb-82 PET MPI, and during tracer production and QC. To estimate dose to the staff in the event of a medical emergency, a survey meter was placed in close contact with the patient during Rb-82 infusion and imaging, and immediately after administration for Tc-99m SPECT. RESULTS: Mean (SD) whole-body effective dose to staff during a single MPI procedure was 0.4 (0.4) µSv for Rb-82 PET (1110 MBq) and 3.3 (1.7) µSv for Tc-99m SPECT (350 MBq). Staff effective dose during tracer production and QC was low (<0.2 µSv/patient) and comparable between tracers. An additional effective dose was measured at close contact to the patient during, and immediately after, tracer administration, although this will not pose a significant radiation risk to staff with either technique as long as this is not routine practice. CONCLUSION: There is a significant reduction in effective dose during Rb-82 PET when compared with Tc-99m SPECT MPI because of the short half-life of Rb-82 and reduced patient contact.