Bacteria‐Assisted Activation of Antimicrobial Polypeptides by a Random‐Coil to Helix Transition

Abstract

The application of antimicrobial peptides (AMPs) is largely hindered by their non-specific toxicity against mammalian cells, which is usually associated with helical structure, hydrophobicity, and charge density. A random coil-to-helix transition mechanism has now been introduced into the design of AMPs, minimizing the toxicity against mammalian cells while maintaining high antimicrobial activity. By incorporating anionic phosphorylated tyrosine into the cationic polypeptide, the helical structure of AMPs was distorted owing to the side-chain charge interaction. Together with the decreased charge density, the AMPs exhibited inhibited toxicity against mammalian cells. At the infectious site, the AMPs can be activated by bacterial phosphatase to restore the helical structure, thus contributing to strong membrane disruptive capability and potent antimicrobial activity. This bacteria-activated system is an effective strategy to enhance the therapeutic selectivity of AMPs.

Universal Scaffold for an Activatable Photosensitizer with Completely Inhibited Photosensitivity

“…The above results suggested that endogenous ALP selectively triggered the conversion of ALP PS into PS Se‐I with an “off‐on” activation of the photosensitized 1 O 2 generation, and thus induced cell death upon light irradiation within the therapeutic window. Since ALP is known to be overproduced in many types of cancer cells and bacteria, ALP PS could be used as a promising activatable photosensitizer for specific ablation of tumor and bacteria.…”

Recent Advances and Future Prospects on Adaptive Biomaterials for Antimicrobial Applications

“…The conventional α‐helical AMPs may lead to adverse peptide interactions with plasma proteins and suffer from a fast clearance from the bloodstream . To balance the bioaccessibility and bactericidal efficacy, Cheng and Xiong et al developed a series of secondary structure transitionable polypeptides for infection control . A class of pH‐sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT‐AMPs) were developed, which bear randomly presented anionic carboxyl groups and cationic poly(γ‐6‐ N ‐(methyldihexylammonium)hexyl‐ l ‐glutamate) (PHLG‐MHH) residues.…”

“…For example, the poly(g‐6‐( N , N ‐dimethyl‐ N ‐octylamino)hexyl‐ l ‐glutamate)‐r‐(poly‐ l ‐tyrosine) (PHOT) was modified via phosphorylation of the phenol residues of tyrosine, changing its secondary structure from helical to random coil. The bacterial phosphatases secreted from Bacillus cereus or S. aureus can efficiently hydrolyze the phosphates, subsequently returning structures of polypeptides back to helical with an enhanced bactericidal efficacy (Figure B) . Taken together, the adaptive secondary structure transitional polypeptides provided an efficient alternative path way to balance the toxicity and the bactericidal activity of a polymer and possess great potential in clinical transition.…”

“…B) Illustration of PHOPT, which adopts a random coil conformation with low toxicity, and PHOT, which adopts a helical conformation with high antimicrobial activity. Reproduced with permission . Copyright 2017, Wiley‐VCH.…”

“…Besides acidity, infection sites are often enriched with bacterial metabolic enzymes and virulence factors. For instance, β-galactosidases, [29] alkaline phosphatases (ALPs), [30,31] nitroreductases, [32] proteinases, [33] lipases, [34][35][36][37] phospholipases, [38] toxins, [39,40] and hyaluronidases [41] may exhibit specifically at the infection sites and are crucial for the bacterial metabolism and survival inside their hosts. Exemplary reactions involving these enzymes are listed in Table 2, most of which are hydrolytic reactions.…”