Antibacterial Activity of Polymers: Discussions on the Nature of Amphiphilic Balance

The purpose of this Viewpoint is to discuss the molecular design principles that guide development of synthetic antimicrobial polymers, especially those intended to mimic the structure of host defense peptides (HDPs). In particular, we focus on the principle of “amphiphilic balance” as it relates to some recently developed polyphosphoniums with somewhat atypical structure. We find that the fundamental concept of amphiphilic balance is still applicable to these new polymers, but that the method to achieve such balance is somewhat unique. We then briefly outline the future challenges and opportunities in this field.     

Cytochrome‐P450‐Induced Ordering of Microsomal Membranes Modulates Affinity for Drugs

Although membrane environment is known to boost drug metabolism by mammalian cytochrome P450s, the factors that stabilize the structural folding and enhance protein function are unclear. In this study, we use peptide‐based lipid nanodiscs to “trap” the lipid boundaries of microsomal cytochrome P450 2B4. We report the first evidence that CYP2B4 is able to induce the formation of raft domains in a biomimetic compound of the endoplasmic reticulum. NMR experiments were used to identify and quantitatively determine the lipids present in nanodiscs. A combination of biophysical experiments and molecular dynamics simulations revealed a sphingomyelin binding region in CYP2B4. The protein‐induced lipid raft formation increased the thermal stability of P450 and dramatically altered ligand binding kinetics of the hydrophilic ligand BHT. These results unveil membrane/protein dynamics that contribute to the delicate mechanism of redox catalysis in lipid membrane.     

Vancomycin‐Dependent Response in Live Drug‐Resistant Bacteria by Metabolic Labeling

The surge in drug‐resistant bacterial infections threatens to overburden healthcare systems worldwide. Bacterial cell walls are essential to bacteria, thus making them unique targets for the development of antibiotics. We describe a cellular reporter to directly monitor the phenotypic switch in drug‐resistant bacteria with temporal resolution. Vancomycin‐resistant enterococci (VRE) escape the bactericidal action of vancomycin by chemically modifying their cell‐wall precursors. A synthetic cell‐wall analogue was developed to hijack the biosynthetic rewiring of drug‐resistant cells in response to antibiotics. Our study provides the first in vivo VanX reporter agent that responds to cell‐wall alteration in drug‐resistant bacteria. Cellular reporters that reveal mechanisms related to antibiotic resistance can potentially have a significant impact on the fundamental understanding of cellular adaption to antibiotics.     

Selective Engineering of Linkage‐Specific α2,6‐N‐Linked Sialoproteins Using Sydnone‐Modified Sialic Acid Bioorthogonal Reporters

The metabolic oligosaccharide engineering (MOE) strategy using unnatural sialic acids has recently enabled the visualization of the sialome in living systems. However, MOE only reports on global sialylation and dissected information regarding subsets of sialosides is missing. Described here is the synthesis and utilization of sialic acids modified with a sydnone reporter for the metabolic labeling of sialoconjugates. The positioning of the reporter on the sugar significantly altered its metabolic fate. Further in vitro enzymatic assays revealed that the 9‐modified neuraminic acid is preferentially accepted by the sialyltransferase ST6Gal‐I over ST3Gal‐IV, leading to the favored incorporation of the reporter into linkage‐specific α2,6‐N‐linked sialoproteins. This sydnone sugar presents the possibility of investigating the roles of specific sialosides.     

Structural and theoretical characterization of a new twisted 4′‐substituted terpyridine compound: 4′‐(isoquinolin‐4‐yl)‐2,2′:6′,2′′‐terpyridine

4′‐Substituted derivatives of 2,2′:6′,2′′‐terpyridine with N‐containing heteroaromatic substituents, such as pyridyl groups, might be able to coordinate metal centres through the extra N‐donor atom, in addition to the chelating terpyridine N atoms. The incorporation of these peripheral N‐donor sites would also allow for the diversification of the types of noncovalent interactions present, such as hydrogen bonding and π–π stacking. The title compound, C₂₄H₁₆N₄, consists of a 2,2′:6′,2′′‐terpyridine nucleus (tpy), with a pendant isoquinoline group (isq) bound at the central pyridine (py) ring. The tpy nucleus deviates slightly from planarity, with interplanar angles between the lateral and central py rings in the range 2.24 (7)–7.90 (7)°, while the isq group is rotated significantly [by 46.57 (6)°] out of this planar scheme, associated with a short H_tpy…H_isq contact of 2.32 Å. There are no strong noncovalent interactions in the structure, the main ones being of the π–π and C—H…π types, giving rise to columnar arrays along [001], further linked by C—H…N hydrogen bonds into a three‐dimensional supramolecular structure. An Atoms In Molecules (AIM) analysis of the noncovalent interactions provided illuminating results, and while confirming the bonding character for all those interactions unquestionable from a geometrical point of view, it also provided answers for some cases where geometric parameters are not informative, in particular, the short H_tpy…H_isq contact of 2.32 Å to which AIM ascribed an attractive character.