Antimicrobial Guanidinylate Polycarbonates Show Oral In Vivo Efficacy Against Clostridioides Difficile.

The emerging antibiotic resistance has been named by the World Health Organization (WHO) as one of the top 10 threats to public health. Notably, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) are designated as serious threats, whereas Clostridioides difficile (C. difficile) is recognized as one of the most urgent threats to human health and unmet medical need. Herein, they report the design and application of novel biodegradable polymers - the lipidated antimicrobial guanidinylate polycarbonates. These polymers showed potent antimicrobial activity against a panel of bacteria with fast-killing kinetics and low resistance development tendency, mainly due to their bacterial membrane disruption mechanism. More importantly, the optimal polymer showed excellent antibacterial activity against C. difficile infection (CDI) in vivo via oral administration. In addition, compared with vancomycin, the polymer demonstrated a much-prolonged therapeutic effect and virtually diminished recurrence rate of CDI. The convenient synthesis, easy scale-up, low cost, as well as biodegradability of this class of polycarbonates, together with their in vitro broad-spectrum antimicrobial activity and orally in vivo efficacy against CDI, suggest the great potential of lipidated guandinylate polycarbonates as a new class of antibacterial biomaterials to treat CDI and combat emerging antibiotic resistance.

Construction of metallo-helicoids with high antimicrobial activity via intermolecular coordination.

Metallo-helicoids are constructed by intermolecular coordination interactions between covalent linear polymer and tritopic/hexatopic molecular templates. These metallo-polymers with helicoidal conformation exhibit high antimicrobial activities against both Gram-positive and Gram-negative pathogens.

Short, Lipidated Dendrimeric γ-AApeptides as New Antimicrobial Peptidomimetics.

Antibiotic resistance is one of the most significant issues encountered in global health. There is an urgent demand for the development of a new generation of antibiotic agents combating the emergence of drug resistance. In this article, we reported the design of lipidated dendrimeric γ-AApeptides as a new class of antimicrobial agents. These AApeptides showed excellent potency and broad-spectrum activity against both Gram-positive bacteria and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The mechanistic studies revealed that the dendrimeric AApeptides could kill bacteria rapidly through the permeabilization of bacterial membranes, analogous to host-defense peptides (HDPs). These dendrimers also did not induce antibiotic resistance readily. The easy access to the synthesis, together with their potent and broad-spectrum activity, make these lipidated dendrimeric γ-AApeptides a new generation of antibacterial agents.

The discovery of cyclic γ-AApeptides as the promising ligands targeting EP2.

EP2 is a G protein-coupled receptor for prostaglandin E2 (PGE2) derived from cell membrane-released arachidonic acid upon various harmful and injurious stimuli. It is commomly upregulated in tumors and injured brain tissues, as its activation by PGE2 is widely believed to be involved in the pathophysiological mechanisms underlying these conditions via promoting pro-inflammatory reactions. Herein, we report the discovery of two novel macrocyclic peptidomimetics based on the screening of a cyclic γ-AApeptides combinatorial library. These two cyclic γ-AApeptides showed excellent binding affinity with the EP2 protein, and they may lead to the development of novel therapeutic agents and/or molecular probes to modulate the PGE2/EP2 signaling.

Development of lipidated polycarbonates with broad-spectrum antimicrobial activity.

Antimicrobial resistance is a global challenge owing to the lack of discovering effective antibiotic agents. Antimicrobial polymers containing the cationic groups and hydrophobic groups which mimic natural host-defense peptides (HDPs) show great promise in combating bacteria. Herein, we report the synthesis of lipidated polycarbonates bearing primary amino groups and hydrophobic moieties (including both the terminal long alkyl chain and hydrophobic groups in the sequences) by ring-opening polymerization. The hydrophobic/hydrophilic group ratios were adjusted deliberately and the lengths of the alkyl chains at the end of the polymers were modified to achieve the optimized combination for the lead polymers, which exhibited potent and broad-spectrum bactericidal activity against a panel of Gram-positive and Gram-negative bacteria. The polymers only showed very limited hemolytic activity, demonstrating their excellent selectivity. Comprehensive analyses using biochemical and biophysical assays revealed the strong interaction between the polymers and bacteria membranes. Moreover, the polymers also showed strong biofilm inhibition activity and did not readily induce antibiotic resistance. Our results suggest that lipidated polycarbonates could be a new class of antimicrobial agents.

Inhibition of the Ubiquitin Transfer Cascade by a Peptidomimetic Foldamer Mimicking the E2 N-Terminal Helix.

The enzymatic cascades for ubiquitin transfer regulate key cellular processes and are the intense focus of drug development for treating cancer and neurodegenerative diseases. E1 is at the apex of the UB transfer cascade, and molecules inhibiting E1 have shown promising activities against cancer cell proliferation. Compared to small molecules, peptidomimetics have emerged as powerful tools to disrupt the protein-protein interactions (PPI) with less drug resistance and high stability in the cell. Herein, we harnessed the D-sulfono-γ-AA peptide to mimic the N-terminal helix of E2 and thereby inhibit E1-E2 interaction. Two stapled peptidomimetics, M1-S1 and M1-S2, were identified as effective inhibitors to block UB transfer from E1 to E2, as shown by in vitro and cellular assays. Our work suggested that PPIs with the N-terminal helix of E2 at the E1-E2 and E2-E3 interfaces could be a promising target for designing inhibitors against protein ubiquitination pathways in the cell.

Metschnikowia sinensis sp. nov., Metschnikowia zizyphicola sp. nov. and Metschnikowia shanxiensis sp. nov., novel yeast species from jujube fruit.

Eight yeast strains were isolated from jujube fruit surfaces collected in Shanxi and Shandong Provinces, China. All eight strains produced needle-shaped ascospores under suitable conditions. Three separate groups, representing three novel species in the genus Metschnikowia, were recognized by sequence comparisons of the 26S rDNA D1/D2 domain and internal transcribed spacer (ITS) region. The names Metschnikowia sinensis sp. nov. (type strain XY103(T)=AS 2.3110(T)=CBS 10357(T)), Metschnikowia zizyphicola sp. nov. (type strain XY201(T)=AS 2.3111(T)=CBS 10358(T)) and Metschnikowia shanxiensis sp. nov. (type strain XY801(T)=AS 2.3112(T)=CBS 10359(T)) are proposed for the three novel species. Phylogenetic analysis of the 26S rDNA D1/D2 domain sequence showed that these three novel species are clustered in a clade together with the previously described species Metschnikowia fructicola, Metschnikowia andauensis, Metschnikowia pulcherrima and Metschnikowia chrysoperlae.