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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Bacterial type I toxin–antitoxin (TA) systems are widespread, and consist of a stable toxic peptide whose expression is monitored by a labile RNA antitoxin. We characterized Staphylococcus aureus SprA2/SprA2 AS module, which shares nucleotide similarities with the SprA1/SprA1 AS TA system. We demonstrated that SprA2/SprA2 AS encodes a functional type I TA system, with the cis -encoded SprA2 AS antitoxin acting in trans to prevent ribosomal loading onto SprA2 RNA. We proved that both TA systems are distinct, with no cross-regulation between the antitoxins in vitro or in vivo . SprA2 expresses PepA2, a toxic peptide which internally triggers bacterial death. Conversely, although PepA2 does not affect bacteria when it is present in the extracellular medium, it is highly toxic to other host cells such as polymorphonuclear neutrophils and erythrocytes. Finally, we showed that SprA2 AS expression is lowered during osmotic shock and stringent response, which indicates that the system responds to specific triggers. Therefore, the SprA2/SprA2 AS module is not redundant with SprA1/SprA1 AS , and its PepA2 peptide exhibits an original dual mode of action against bacteria and host cells. This suggests an altruistic behavior for S. aureus in which clones producing PepA2 in vivo shall die as they induce cytotoxicity, thereby promoting the success of the community.

International audienceThe effect of the streaming current flowing through the porous structure of composite membranes during tangential electrokinetic measurements was investigated. It was shown that neglecting this additional path for streaming current may have dramatic implications in the interpretation of the experimental data and on the determination of the membrane zeta potential. Experimental measurements of both streaming current and electrical conductance were performed with two different composite polymer membranes. By following the procedure proposed by Yaroshchuk and Luxbacher, Langmuir 26 (2010) 10882-10889, in the present work it was possible to determine separately the zeta potential of the membrane surfaces and that of their underlying porous structures. This experimental procedure was shown to provide useful information on the functionalization of an ultrafiltration polyethersulfone membrane by positively charged 4-benzyltriphenylphosphonium groups. Notably we found that the chemical modification leads to a charge reversal (from negative to positive) of the porous substructure of the membrane while the overall charge of the external surface remains negative, although with diminished magnitude

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The halogen bonding ability of ditopic halogen bond donors can be assessed from the maximum value of the molecular surface electrostatic potential, called σ-hole, at the two halogen atoms. We show here that in N,N′-diodo-dimethylhydantoin (DIH), the halogen bonding (XB) ability of the two nitrogen-bound iodine atoms does not parallel the calculated σ-hole amplitude. The cocrystallization of DIH with a series of para-substituted pyridines, noted Py-R (R = pyrrolidinyl, NMe2, Me, H, CO2Me, CF3, CN), affords bis-adducts DIH·(Py-R)2 with the more electron-rich pyridines, while mono-adducts DIH·(Py-R) are favored with the more electron-poor pyridines (R = CO2Me, CF3, CN). Analysis of the structural characteristics of these mono- and bis-adducts, combined with theoretical calculations, demonstrates that the formation of a first N–I···N′Py‑R XB deeply modifies the XB ability (and associated σ-hole) of the second uncoordinated iodine atom. Under these conditions, the latter might associate through I···O XB to the carbonyl oxygen atom of a neighboring mono-adduct in the crystal rather than to a second pyridine. These studies show that when working with polytopic XB donors, one should always consider the deactivation of the remaining halogen atoms following sequential XB formation.

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