A library of oligothiophenes with precisely controlled chain length, regioregularity, sequence, and pendant functionality in the side chains, were prepared by iterative convergent/divergent organometallic couplings. The cationic and facially amphiphilic structures were designed to mimic the salient physiochemical features of host defense peptides (HDPs) while concurrently exerting a photodynamic mechanism of antibacterial activity. In the dark, the oligothiophenes exert broad-spectrum and rapid bactericidal activity in the micromolar regime, which is the typical range of HDP activity. Under visible light, the antibacterial potency is enhanced by orders of magnitude, leading to potency in the nano-molar concentration range, whereas the toxicity to red blood cells is almost unaffected by the same visible light exposure. We attribute the potent and selective antibacterial activity to a dual mechanism of action that involves bacterial cell binding, combined with ROS production in the bound state. Comonomer sequence and chain length dispersity play important roles in dictating the observed biological activities. The most promising candidate compound from a set of screening experiments showed antibacterial activity that is three orders of magnitude more potent against bacteria relative to toxicity against RBCs. Thus, we have established a new class of HDP-mimetic antibacterial compounds with nanomolar activity and cell type selectivity of greater than 1300-fold. These and related compounds may be highly promising candidates in the urgent search for new topical photodynamic antibacterial formulations.

Sequence and dispersity as determinants of photodynamic antibacterial activity exerted by peptidomimetic oligo(thiophene)s

2019 Spring National Meeting

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