Inverse Polyamidoamine (i-PAMAM) Dendrimer Antimicrobials

Here we redesigned the branches of polyamidoamine (PAMAM) dendrimers by moving the amide carbonyl group on the other side of the amide nitrogen atom, transforming the beta-alaninyl-amidoethylamine branch, which easily undergoes retro-Michael reactions and renders PAMAMs intrinsically unstable, into a more stable glycyl-amidopropylamine branch. The resulting inverse PAMAM (i-PAMAM) dendrimers have the same carbon framework as PAMAMs and only differ by the position of the carbonyl group. In contrast to PAMAMs which are prepared in solution and are difficult to purify, we synthesize i-PAMAMs using high-temperature solid-phase peptide synthesis by iterative coupling and deprotection of the commercially available N,N-bis(N '-Fmoc-3-aminopropyl)glycine and purify them preparative reverse phase HPLC. Our i-PAMAM dendrimers show no detectable degradation over time. We demonstrate this new class of dendrimers with the synthesis of antimicrobial dendrimers with potent yet non-membrane disruptive activities against both Gram-negative and Gram-positive bacteria.

Automated summary

We redesigned the branches of PAMAM dendrimers to improve their stability by modifying the amide carbonyl group. The resulting i-PAMAM dendrimers have the same carbon framework as PAMAMs but differ in the position of the carbonyl group. Compared to PAMAMs, which are difficult to purify, we synthesized i-PAMAMs using solid-phase peptide synthesis and purified them using preparative reverse phase HPLC. Our i-PAMAM dendrimers showed no degradation over time and exhibited potent antimicrobial activities against both Gram-negative and Gram-positive bacteria.