There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure-function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.

We report the identification of a new class of antimicrobial peptidomimetics-γ-AApeptides with potent and broad-spectrum activity, including clinically-relevant strains that are unresponsive to most antibiotics. They are also not prone to select for drug-resistance.

Antimicrobial drug resistance is one of the greatest threats facing mankind. Antimicrobial peptides (AMPs) can potentially circumvent drug resistance, probably through a bacterial membrane-disruption mechanism. However, they suffer from low in vivo stability, potential immunogenicity, and difficulty in optimization. The development of antimicrobial peptidomimetics is therefore an emerging research area as they avoid the potential disadvantages of AMPs. Cyclic peptidomimetics are of significant interest since constraints induced by cyclization are expected to further improve their antimicrobial activity. Nonetheless, the report of cyclic oligomeric peptidomimetics for antimicrobial development is rare. Herein, for the first time, we report the design and synthesis of cyclic g-AApeptides via an on-resin cyclization. These cyclic g-AApeptides are potent and broad-spectrum active against fungus and multidrug resistant Gram-positive and Gram-negative bacterial pathogens. Our results demonstrate the potential of cyclic g-AApeptides as a new class of antibiotics to circumvent drug resistance by mimicking the bactericidal mechanism of AMPs. Meanwhile, the facile synthesis of cyclic g-AApeptides may further expand the applications of g-AApeptides in biomedical sciences.

Antimicrobial peptides (AMPs) are host-defense agents capable of both bacterial membrane disruption and immunomodulation. However, the development of natural AMPs as potential therapeutics is hampered by their moderate activity and susceptibility to protease degradation. Herein we report lipidated cyclic γ-AApeptides that have potent antibacterial activity against clinically relevant Gram-positive and Gram-negative bacteria, many of which are resistant to conventional antibiotics. We show that lipidated cyclic γ-AApeptides mimic the bactericidal mechanism of AMPs by disrupting bacterial membranes. Interestingly, they also harness the immune response and inhibit lipopolysaccharide (LPS) activated Toll-Like Receptor 4 (TLR4) signaling, suggesting that lipidated cyclic γ-AApeptides have dual roles as novel antimicrobial and anti-inflammatory agents.

We report a new class of peptide mimetics, α-AApeptides, that display broad-spectrum activity against both Gram-negative and Gram-positive bacteria and fungi. With non-hemolytic activity, resistance to protease hydrolysis, and easy sequence programmability, α-AApeptides may emerge as a novel class of antibiotics.

The last two decades have seen the rise of antimicrobial peptides (AMPs) to combat emerging antibiotic resistance. Herein we report the solid phase synthesis of short lipidated α/γ-AA hybrid peptides. This family of lipo-chimeric peptidomimetics displays potent and broad-spectrum antimicrobial activity against a range of multi-drug resistant Gram-positive bacteria and Gram-negative bacteria. These lipo-α/γ-AA hybrid peptides also demonstrate high biological specificity, with no hemolytic activity towards red blood cells. Fluorescence microscopy suggests that these lipo-α/γ-AA chimeric peptides can mimic the mode of action of AMPs and kill bacterial pathogens via membrane disintegration. As the composition of these chimeric peptides is simple, therapeutic development may be economically feasible, and amenable for a variety of antimicrobial applications.

There has been significant interest in the development of antimicrobial cationic polymers due to their low manufacture cost and ease of synthesis compared to small antimicrobial peptides (AMPs). These polymers are designed to mimic amphiphilic structures of AMPs which can disrupt negatively charged bacterial membranes, and can therefore lead to potential antibiotic agents to fight emerging drug resistance. However, the reports of biodegradable antimicrobial polymer nanoparticles are rare. Herein we report the development of antimicrobial PEG-poly(amino acid)s. Some of these multi-block PEG-poly(amino acid)s form defined nanoparticles in solution, and display potent and broad-spectrum antimicrobial activity. Fluorescence and SEM studies show that these polymers are likely to kill bacteria by disrupting bacterial membranes. As these polymers are biodegradable and easy to scale up, they may provide an attractive approach for the development of antibiotic agents.

We report a series of lipidated α-AApeptides that mimic the structure and function of natural antimicrobial lipopeptides. Several short lipidated α-AApeptides show broadspectrum activity against a range of clinically related Grampositive and Gram-negative bacteria as well as fungus. Their antimicrobial activity and selectivity are comparable or even superior to the clinical candidate pexiganan as well as previously reported linear α-AApeptides. The further development of lipidated α-AApeptides will lead to a new class of antibiotics to combat drug resistance. KEYWORDS: antimicrobial peptides, peptidomimetics, drug resistance, lipidation, α-AApeptides A ntimicrobial peptides (AMPs) are found in most living organisms as an integral component of their innate defense against invading pathogens.1,2 Unlike conventional antibiotics that target specific substrates involved in bacterial metabolism, AMPs are believed to kill bacteria via a nonspecific interaction with their membranes, which has less chance of inducing the development of resistance by bacteria.1,2 Short cationic amphiphilic AMPs tend to interact with the negatively charged phospholipids on the bacterial membrane, which accounts for their selectivity for bacteria against eukaryotic cells whose membranes are more zwitterionic.3,4 Because of their selectivity for bacteria, low propensity for development of drug resistance, and broad-spectrum antimicrobial potency, AMPs are considered an emerging class of antimicrobial agents. 1−3 Nevertheless, the therapeutic application of AMPs is impeded by their intrinsic instability in the context of proteolytic degradation.1,2 Bactericidal peptidomimetics comprised of unnatural amino acids were thereby developed to circumvent the drawbacks of AMPs, which are protease-resistant and of improved bioavailability. 5 In recent years, several peptidomimetic analogues of AMPs, such as β-peptides, 6−9 arylamides, 10,11 and peptoids, 3,12,13 have received significant research interest.Lipidated peptides such as polymyxin B 14 and daptomycin 15 are lipo-antibiotics, which possess fatty acid tails that are integral to their bactericidal activities. It has been shown that attachment of saturated linear fatty acids to peptide termini greatly enhanced AMPs' antimicrobial activities toward both Gram-positive and Gram-negative strains. 16−19 More recently, short peptoid mimetics alkylated with lipids of 10 or 13 carbons were demonstrated to bear improved selectivity, without losing any antimicrobial activities. 13 It was suspected that lipid alkylation improves the hydrophobicity of charged peptides 18 and facilitates the interaction with cytoplasmic membranes.18 It is thereby envisioned that the development of lipidated peptidomimetics may overcome some of the drawbacks associated with current lipopeptide antibiotics. Herein, we report the development of lipidated α-AApeptides as potential antimicrobial agents. We have recently developed a novel class of peptidomimetics based on the α-chiral PNA (peptide nucleic acid) back...