There is great need for stand-alone luminescence-based chemosensors that exemplify selectivity, sensitivity, and applicability and that overcome the challenges that arise from complex, real-world media. Discussed herein are recent developments toward these goals in the field of supramolecular luminescent chemosensors, including macrocycles, polymers, and nanomaterials. Specific focus is placed on the development of new macrocycle hosts since 2010, coupled with considerations of the underlying principles of supramolecular chemistry as well as analytes of interest and common luminophores. State-of-the-art developments in the fields of polymer and nanomaterial sensors are also examined, and some remaining unsolved challenges in the area of chemosensors are discussed.

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Supramolecular Luminescent Sensors

Bacterial infections and antibiotic resistance, particularly by Gram-negative pathogens, have become a global healthcare crisis. We report the design of a class of cationic antimicrobial polymers that cluster local facial amphiphilicity from repeating units to enhance interactions with bacterial membranes without requiring a globally conformational arrangement associated with highly unfavorable entropic loss. This concept of macromolecular architectures is demonstrated with a series of multicyclic natural product-based cationic polymers. We have shown that cholic acid derivatives with three charged head groups are more potent and selective than lithocholic and deoxycholic counterparts, particularly against Gram-negative bacteria. This is ascribed to the formation of true facial amphiphilicity with hydrophilic ion groups oriented on one face and hydrophobic multicyclic hydrocarbon structures on the opposite face. Such local facial amphiphilicity is clustered via a flexible macromolecular backbone in a concerted way when in contact with bacterial membranes.

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Macromolecular-clustered facial amphiphilic antimicrobials.

The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.

https://www.mdpi.com/1420-3049/22/9/1430/pdf

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

Antimicrobial resistance (AMR) is one of the greatest threats to human health that, by 2050, will lead to more deaths from bacterial infections than cancer. New antimicrobial agents, both broad-spectrum and selective, that do not induce AMR are urgently required. Antimicrobial peptides (AMPs) are a novel class of alternatives that possess potent activity against a wide range of Gram-negative and positive bacteria with little or no capacity to induce AMR. This has stimulated substantial chemical development of novel peptide-based antibiotics possessing improved therapeutic index. This review summarises recent synthetic efforts and their impact on analogue design as well as their various applications in AMP development. It includes modifications that have been reported to enhance antimicrobial activity including lipidation, glycosylation and multimerization through to the broad application of novel bio-orthogonal chemistry, as well as perspectives on the direction of future research. The subject area is primarily the development of next-generation antimicrobial agents through selective, rational chemical modification of AMPs. The review further serves as a guide toward the most promising directions in this field to stimulate broad scientific attention, and will lead to new, effective and selective solutions for the several biomedical challenges to which antimicrobial peptidomimetics are being applied.

Chemically modified and conjugated antimicrobial peptides against superbugs.

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.

Poly(2-Oxazoline)-Based Functional Peptide Mimics: Eradicating MRSA Infections and Persisters while Alleviating Antimicrobial Resistance.

ConspectusThe development of sequence-specific peptidomimetics has led to a variety of fascinating discoveries in chemical biology. Many peptidomimetics can mimic primary, secondary, and even tertiary structure of peptides and proteins, and because of their unnatural backbones, they also possess significantly enhanced resistance to enzymatic hydrolysis, improved bioavailability, and chemodiversity. It is known that peptide nucleic acids (PNAs) are peptidic sequences developed for the mimicry of nucleic acids; however, their unique backbone as the molecular scaffold of peptidomimetics to mimic structure and function of bioactive peptides has not been investigated systematically. As such, we recently developed a new class of peptidomimetics, “γ-AApeptides”, based on the chiral γ-PNA backbone. They are termed γ-AApeptides because they are the oligomers of γ-substituted-N-acylated-N-aminoethyl amino acids. Similar to other classes of peptidomimetics, γ-AApeptides are also resistant to proteolytic degradation ...

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γ-AApeptides: Design, Structure, and Applications

Infections caused by multidrug-resistant bacteria have emerged in recent decades, leading to escalating interest in host defense peptides (HDPs) to reverse this dangerous trend Inspired by the modular design in bioengineering, herein we report a new class of small amphiphilic scorpionlike peptidomimetics based on this strategy These HDP mimics show potent antimicrobial activity against both Gram-positive and Gram-negative bacteria without drug resistance but with a high therapeutic index The membrane-compromising action mode was suggested to be their potential bactericidal mechanism Pharmacodynamic experiments were conducted using a murine abscess model of methicillin-resistant Staphylococcus aureus (MRSA) infections The lead compound 12 showed impressive in vivo therapeutic efficacy with ∼99998% (47log) reduction in skin MRSA burden, a significantly higher bactericidal efficiency than ciprofloxacin, and good biocompatibility These results highlight the potential of these HDP mimics as novel antibiotic therapeutics

Modular Design of Membrane-Active Antibiotics: From Macromolecular Antimicrobials to Small Scorpionlike Peptidomimetics.

The hyperactive energy metabolism mostly contributes the tumor cells growth and proliferation. Herein, the intelligent nanoparticles (P-B-D NPs) obtained by loading BAY-876 and doxorubicin (Dox)-Duplex into nanoparticles composed of disulfide bond (SS) containing polymer are reported, which provide an efficient resistance of tumor cells energy metabolism and tumor growth to conquer malignant tumor. In response to the reducing microenvironment of tumor tissue, the SS bond can be disintegrated by intracellular glutathione to block the synthesis of lipid repair enzyme-glutathione peroxidase 4 for ferroptosis therapy. More importantly, the released BAY-876 can inhibit the functionality of glucose transporter 1, restricting the glucose uptake of tumor cells to a low energy metabolism status. Meanwhile, Dox-Duplex can interact with ATP to reduce intracellular ATP content and release Dox to kill tumor cells. Collectively, this work offers a new idea for restricting tumor cells energy metabolism to inhibit their proliferation.

The Sustainability of Energy Conversion Inhibition for Tumor Ferroptosis Therapy and Chemotherapy

https://par.nsf.gov/servlets/purl/10158144

Antibacterial activity of lipo-α/sulfono-γ-AA hybrid peptides

We report an efficient method for the preparation of unprecedented head-to-tail cyclic sulfono-γ-AApeptides. Following this method, a number of cyclic sequences bearing two to five subunits were efficiently synthesized. In addition, the X-ray crystal structure study of a three-membered cyclic sulfono-γ-AApeptide revealed a type II β-turn-like character.

Lulu Wei

Papers

γ-AApeptides: Design, Structure, and Applications

Modular Design of Membrane-Active Antibiotics: From Macromolecular Antimicrobials to Small Scorpionlike Peptidomimetics.

The Sustainability of Energy Conversion Inhibition for Tumor Ferroptosis Therapy and Chemotherapy

Antibacterial activity of lipo-α/sulfono-γ-AA hybrid peptides

The synthesis of head-to-tail cyclic sulfono-γ-AApeptides