Session: Current Topics in Biological Chemistry:

Finding drugs that act synergistically against a pathogen is one way of combating antimicrobial resistance because it offers a number of benefits including lower dosages for each drug and improved activity. Several organisms produce multiple types of antimicrobial peptides and they are hypothesized to act synergistically in order to combat different types of infections that the organism might encounter and to slow down the emergence of resistant strains. The solitary tunicate, Styela clava, produces a number of antimicrobial peptides as part of its innate defense against microorganisms. Among these are the six α-helical, amphipathic AMPs belonging to the Clavanin family. In this study, the six members of this family of AMPs (Clavanin A-E and Clavaspirin) were synthesized and evaluated for synergy against Escherichia coli using the checkerboard assay and subsequent calculation of the fractional inhibitory concentration (FIC). It was found that Clavanin A synergizes with Clavanin B and Clavanin D synergizes with Clavaspirin. Clavanin E has an additive effect on all other Clavanins except Clavanin D. Results are consistent when the AMP-AMP combinations are applied in a broth microdilution assay. All D-amino acid analogs of Clavanin A and Clavanin B were also synthesized and it was noted that there is at least an 8-fold improvement in the MIC of both peptides. Combinations of the L and D analogues of Clavanin A and B are still synergistic when applied together in a checkerboard assay. This improvement in activity could be due to the higher stability against proteolysis of the D-peptides. In this presentation, we will discuss the aforementioned results, discuss plausible mechanisms of action, and the opportunities for drug development based on this chemistry.

Alfredo Angeles Boza

University of Connecticut

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