The rapid increase in the occurrence of multi-drug resistant bacteria emphasizes the need for therapeutic alternatives to commonly available antibiotics. Cyclic peptides (CP’s) with an even number of alternating D- and L-α-amino acids can self-assemble via β-sheet stacking into rod-like nanotubes with distinct properties. These cyclic peptide nanotubes (CPNT’s) appear to be a promising class of potential antimicrobials. However, a major drawback is their lack in selectivity regarding the cell membrane disruption. In this work, a bulky polymethacrylate (p(MPEGMA)) bottle brush copolymer was attached to CPs via a stimulus-responsive linker to decrease non-specific toxicity towards mammalian cells. The linker exhibits a GLA-peptide sequence which can be cleaved selectively by the virulence factor P. aeruginosa elastase (LasB) that is secreted in case of an infection. Hence, the selectivity is supposed to be enhanced without loss of antimicrobial activity. The brush-shaped polymer solubilizes the conjugate and prevents the nanotube formation prior to the cleavage. The targeted conjugates were synthesized and SLS measurements showed that no self-assembly occurs when the polymer is still attached. Linker sequence, as well as the final conjugate were shown to be cleavable in the presence of LasB.

Synthesis of LasB-stimulus-responsive cyclic peptide-polymer-conjugates as potential antimicrobials to combat multi-drug resistant P. aeruginosa infections

256th National Meeting (2018)

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