We compare here the halogen bond characteristics of bimolecular adducts involving either N-bromo- or N-iodosaccharin as strong halogen bond donors, with 4-picoline as a common XB acceptor. In the NBSac·Pic system, the bromine atom of NBSac is displaced toward the picoline, almost at a median position between the two nitrogen atoms, N and N', with NBr and BrN' distances at 2.073(6) and 2.098(6) Å respectively. This extreme situation contrasts with the analogous iodine derivative, NISac·Pic, where the N-I and IN' distances amount to 2.223(4) and 2.301(4) Å respectively. Periodic DFT calculations, and molecular calculations of adducts (PBEPBE-D2 aug-cc-pVTZ) either at the experimental frozen geometry or with optimization of the halogen position, indicate a more important degree of covalency (i.e. shared-shell character) in the adduct formed with the bromine atom. A stronger charge transfer to the picoline is also found for the bromine (+0.27 |e|) than for the iodine (+0.18 |e|) system. This inversion of halogen bond strength between I and Br finds its origin in the strong covalent character of the interaction in these adducts, in line with the strength of covalent N-Br and N-I bonds. Detailed characterization of the critical points (CPs) of the L(r) = -∇ρ(r) function along bonding directions has permitted the adducts to be distinguished and they can be respectively described as "neutral" NISac/Pic and "intermediate" NSac/Br/Pic, the latter with Br being close to formal equivalent NBr and BrN' interactions but still more associated to the XB donor than to the picoline, as indicated by the topological and energetic properties of the ρ(r) function at the bond critical points (BCPs).

Antibiotics are a medical wonder, but an increasing frequency of resistance among most human pathogens is rendering them ineffective. If this trend continues, the consequences for public health and for the general community could be catastrophic. The current clinical pipeline, however, is very limited and is dominated by derivatives of established classes, the “me too” compounds. Here, we have exploited our recent identification of a bacterial toxin to transform it into antibiotics active on multidrug-resistant (MDR) gram-positive and -negative bacterial pathogens. We generated a new family of peptidomimetics—cyclic heptapseudopeptides—inspired from a natural bacterial peptide. Out of the 4 peptides studied, 2 are effective against methicillin-resistant Staphylococcus aureus (MRSA) in mild and severe sepsis mouse models without exhibiting toxicity on human erythrocytes and kidney cells, zebrafish embryos, and mice. These new compounds are safe at their active doses and above, without nephrotoxicity. Efficacy was also demonstrated against Pseudomonas aeruginosa and MRSA in a mouse skin infection model. Importantly, these compounds did not result in resistance after serial passages for 2 weeks and 4 or 6 days’ exposure in mice. Activity of heptapseudopeptides was explained by the ability of unnatural amino acids to strengthen dynamic association with bacterial lipid bilayers and to induce membrane permeability, leading to bacterial death. Based on structure determination, we showed that cationic domains surrounded by an extended hydrophobic core could improve bactericidal activity. Because 2 peptide analogs, Pep 16 and Pep19, are effective against both MRSA and P . aeruginosa in severe sepsis and skin infection models, respectively, we believe that these peptidomimetics are promising lead candidates for drug development. We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.

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