Peptides have important biological functions. However, their susceptibility to proteolysis limits their applications. We demonstrated here for the first time, that poly(2‐oxazoline) (POX) can work as a functional mimic of peptides. POX‐based glycine pseudopeptides, a host defense peptide mimic, had potent activities against methicillin‐resistant S. aureus, which causes formidable infections. The POX mimic showed potent activity against persisters that are highly resistant to antibiotics. S. aureus did not develop resistance to POX owning to the reactive oxygen species related antimicrobial mechanism. POX‐treated S. aureus is sensitive to common antibiotics, demonstrating no observable antimicrobial pressure or cross‐resistance in using antimicrobial POX. This study highlights POX as a new type of functional mimic of peptides and opens new avenues in designing and exploring peptide mimetics for biological functions and applications.

Methicillin-Resistant Staphylococcus aureus (MRSA) induced infection calls for antibacterial agents that are not prone to antimicrobial resistance. We prepare protease-resistant peptoid polymers with variable C-terminal functional groups using a ring-opening polymerization of N-substituted N-carboxyanhydrides (NNCA), which can provide peptoid polymers easily from the one-pot synthesis. We study the optimal polymer that displays effective activity against MRSA planktonic and persister cells, effective eradication of highly antibiotic-resistant MRSA biofilms, and potent anti-infectious performance in vivo using the wound infection model, the mouse keratitis model, and the mouse peritonitis model. Peptoid polymers show insusceptibility to antimicrobial resistance, which is a prominent merit of these antimicrobial agents. The low cost, convenient synthesis and structure diversity of peptoid polymers, the superior antimicrobial performance and therapeutic potential in treating MRSA infection altogether imply great potential of peptoid polymers as promising antibacterial agents in treating MRSA infection and alleviating antibiotic resistance.

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug‐resistance. We previously developed amine‐pendent poly(2‐oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium‐pendent POXs, inspired by cell‐penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking β-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial β-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.

Biocompatible and proteolysis-resistant poly-bpeptides have broad applications and are dominantly synthesized via the harsh and water-sensitive ring-opening polymerization of b-lactams in a glovebox or using a Schlenk line, catalyzed by the strong base LiN(SiMe 3 ) 2 . We have developed a controllable and water-insensitive ring-opening polymerization of b-amino acid N-thiocarboxyanhydrides (b-NTAs) that can be operated in open vessels to prepare poly-b-peptides in high yields, with diverse functional groups, variable chain length, narrow dispersity and defined architecture. These merits imply wide applications of b-NTA polymerization and resulting poly-b-peptides, which is validated by the finding of a HDP-mimicking poly-b-peptide with potent antimicrobial activities. The living b-NTA polymerization enables the controllable synthesis of random, block copolymers and easy tuning of both terminal groups of polypeptides, which facilitated the unravelling of the antibacterial mechanism using the fluorophore-labelled poly-b-peptide.Unnatural polypeptides are structurally similar to natural peptides and have prominent advantages in applications owing to their biocompatibility and resistance to proteolysis. [1] Among them, poly-b-peptides have attracted broad interest [1a-c, 2] and have demonstrated great potential in proteinprotein interaction, [3] antimicrobial, [4] glycopeptide mimicking, [5] tissue engineering, [6] constructing molecular brushes, [7] and surface functional coating. [8] In contrast to the polymerization of b-amino acid N-carboxyanhydrides (b-NCAs) for which few follow-up has been reported, [9] ring-opening polymerization (ROP) of b-lactam is the most commonly used method for poly-b-peptides synthesis reported in the literature. [4e,f,h, 5, 6, 10] The advances of LiN(SiMe 3 ) 2 -catalyzed ROP of sidechain-functionalized b-lactams have boosted the functionality and application of poly-b-peptides. [4e,f,h, 5, 6, 10a,d, 11] Nevertheless, this strong basic polymerization condition is not compatible with base-labile groups, such as esters, and has limited the structural diversity and application of poly-bpeptides. In addition, the ROP of b-lactams is extremely sensitive to water and is normally operated in the glovebox using dry solvents even though it is still challenging to prepare long poly-b-peptides over 100 repeating units. [4e,h, 6a, 10a,e] Moreover, the C-terminal modification of sidechain-functionalized poly-b-peptides is notoriously difficult though modification on nonfunctionalized poly-b-peptides was reported previously. [10e,f] These long-lasting shortcomings of poly-b-peptide synthesis urgently call for solutions.Here, we report a convenient synthesis of poly-b-peptides via controllable ROP of b-amino acid N-thiocarboxyanhydrides (b-NTAs), which is insensitive to water and oxygen, and is able to address all aforementioned shortcomings of the currently dominating methods for poly-b-peptide synthesis from b-lactams (Figure 1 a). The ROP of b-NTAs proceeded smoothly under mild condition w...