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.
Multidrug-resistant (MDR) bacteria
have emerged quickly and have caused serious nosocomial infections.
It is urgent to develop novel antimicrobial agents for treating MDR
bacterial infections. In this study, we isolated 45 strains of bacteria
from hospital patients and found shockingly that most of these strains
were MDR to antimicrobial drugs. This inspired us to explore antimicrobial
peptide polymers as synthetic mimics of host defense peptides in combating
drug-resistant bacteria and the formidable antimicrobial challenge.
We found that peptide polymer 80:20 DM:Bu (where DM is a hydrophilic/cationic
subunit and Bu is a hydrophobic subunit) displayed fast bacterial
killing, broad spectrum, and potent activity against clinically isolated
strains of MDR bacteria. Moreover, peptide polymer 80:20 DM:Bu displayed
potent in vivo antibacterial efficacy, comparable
to the performance of polymyxin B, in a Pseudomonas aeruginosa (P. aeruginosa) infected rat full-thickness
wound model. The peptide polymer can be easily synthesized from ring-opening
polymerization with remarkable reproducibility in structural properties
and biological activities. The peptide polymer’s potent and
broad spectrum antimicrobial activities against MDR bacteria in vitro and in vivo, resistance to proteolysis,
and high structural diversity altogether imply a great potential of
peptide polymer 80:20 DM:Bu in antimicrobial applications as synthetic
mimics of host defense peptides.
The high mortality rate of invasive fungal infections and quick emergence of drug-resistant fungal pathogens urgently call for potent antifungal agents. Inspired by the cell penetrating peptide (CPP) octaarginine (R8), we elongated to 28 residues poly(D,L-homoarginine) to obtain potent toxicity against both fungi and mammalian cells. Further incorporation of glutamic acid residues shields positive charge density and introduces partial zwitterions in the obtained optimal peptide polymer that displays potent antifungal activity against drug-resistant fungi superior to antifungal drugs, excellent stability upon heating and UV exposure, negligible in vitro and in vivo toxicity, and strong therapeutic effects in treating invasive fungal infections. Moreover, the peptide polymer is insusceptible to antifungal resistance owing to the unique CPP-related antifungal mechanism of fungal membrane penetration followed by disruption of organelles within fungal cells. All these merits imply the effectiveness of our strategy to develop promising antifungal agents.
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