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Bacterial infectious disease is a serious public health concern throughout the world. Pathogen drug resistance, arising from both rational use and abuse/misuse of germicides, complicates the situation. Aside from developing novel antibiotics and antimicrobial agents, molecular approaches have become another significant method to overcome the problem of pathogen drug resistance. Established supramolecular systems, the antibiotic properties of which can be switched “on” and “off” through host–guest interactions, show great potential in combating issues regarding antibiotic resistance in the long term, as indicated by several recent studies. In this Concept, recently developed strategies for antibacterial regulation are summarized and further directions for research into antibiotic switches are proposed.

99 problems but a switch ain't one: Bacterial infectious disease is a serious public health concern throughout the world. Supramolecular antibiotic systems that can be switched “on” and “off” through host–guest interactions show great potential in combating issues regarding antibiotic resistance in the long term. In this Concept, recently developed strategies for antibacterial regulation are summarized and further research directions are proposed.

Nanoparticles covered with ligand shells comprising both positively and negatively charged ligands exhibit Gram-selective antibacterial action controlled by a single experimental parameter, namely the proportion of [+] and [−] ligands tethered onto these particles. Gram selectivity is attributed to the interplay between polyvalent electrostatic and non-covalent interactions that work in unison to disrupt the bacterial cell wall. The [+/−] nanoparticles are effective in low doses, are non-toxic to mammalian cells, and are tolerated well in mice. These results constitute the first example of rational engineering of Gram selectivity at the (macro)molecular level.

Gram-specific antimicrobial activity: Nanoparticles covered with mixtures of negatively and positively charged ligands in optimal proportions exhibit antibiotic properties that can be engineered specific to either Gram-positive or Gram-negative bacteria. Arrows in the experimental images point to the places at which the particles rupture the bacterial cell wall.

The synthesis of a set of tetrazine-bearing fluorogenic dyes suitable for intracellular labeling of proteins in live cells is presented. The red excitability and emission properties ensure minimal autofluorescence, while through-bond energy-transfer-based fluorogenicity reduces nonspecific background fluorescence of unreacted dyes. The tetrazine motif efficiently quenches fluorescence of the phenoxazine core, which can be selectively turned on chemically upon bioorthogonal inverse-electron-demand Diels–Alder reaction with proteins modified genetically with strained trans-cyclooctenes.

Put a tag on it: The synthesis and bioorthogonal labeling potential of a set of tetrazine-based fluorogenic dyes suitable for intracellular labeling of proteins in live cells is presented (see figure). The red excitability and emission properties ensure minimal autofluorescence, while the through-bond energy-transfer-based fluorogenicity reduces nonspecific background fluorescence of unreacted dyes.

Stapled peptides are an emerging class of cyclic peptide molecules with enhanced biophysical properties such as conformational and proteolytic stability, cellular uptake and elevated binding affinity and specificity for their biological targets. Among the limited number of chemistries available for their synthesis, the cysteine-based stapling strategy has received considerable development in the last few years driven by facile access from cysteine-functionalized peptide precursors. Here we present some recent advances in peptide and protein stapling where the side-chains of cysteine residues are covalently connected with a range of different crosslinkers affording bisthioether macrocyclic peptides of varying topology and biophysical properties. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 843–852, 2016.