The increasing prevalence of antibiotic-resistant bacterial infections, coupled with the decline in the number of new antibiotic drug approvals, has created a therapeutic gap that portends an emergent public health crisis.

Self-immolative polymers (SIMPs) are macromolecules that spontaneously undergo depolymerization into small molecules when triggered by specific external stimuli. We report here the first examples of antimicrobial SIMPs with potent, rapid, and broad-spectrum bactericidal activity. Their antibacterial and hemolytic activities were examined as a function of cationic functionality. Polymers bearing primary ammonium cationic groups showed more potent bactericidal activity against Escherichia coli, relative to tertiary and quaternary ammonium counterparts, whereas the quaternary ammonium polymers showed the lowest hemolytic toxicity. These antibacterial polycations undergo end-to-end depolymerization when triggered by an externally applied stimulus. Specifically, poly(benzyl ether)s end-capped with a silyl ether group and bearing pendant allyl side chains were converted to polycations by photoinitiated thiol-ene radical addition using cysteamine HCl. The intact polycations are stable in solution, but they spontaneously unzip into their component monomers upon exposure to fluoride ions, with excellent sensitivity and selectivity. Upon triggered depolymerization, the antibacterial potency was largely retained but the hemolytic toxicity was substantially reduced. Thus, we reveal the first example of a self-immolative antibacterial polymer platform that will enable antibacterial materials to spontaneously unzip into biologically active small molecules upon the introduction of a specifically designed stimulus.

A library of functionalized oligo(thiophene)s with precisely controlled chain length, regioregularity, sequence, and pendant moieties in the side chains was 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 nanomolar concentration range, whereas the toxicity to red blood cells (RBCs) 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 reactive oxygen species 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 3 orders of magnitude more potent against bacteria relative to toxicity against RBCs. Importantly, this compound did not induce resistance upon 21 subinhibitory passages, whereas the activity of ciprofloxacin was reduced 32× in the same condition. Cytotoxicity against HeLa cells in vitro is orders of magnitude weaker than antibacterial activity under visible light illumination. 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.

Self-immolative polymers, which exert potent antibacterial activity with low hemolytic toxicity to red blood cells, are triggered to unzip into small molecules by a chemical stimulus.