Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

A desymmetrization route to fused Troger's base analogues was developed. In this way, the synthesis of the first example of an anti-anti diastereomer of a fused tris-Troger's base analogue was accomplished. The resulting compound 5b is a nonlinear symmetric regioisomer obtained from p-bromoaniline in 7% yield. The corresponding syn-anti diastereomer 5a was obtained in 4% yield.

The synthesis of an orthogonal topological pentamer analogue of helicene is presented. This analogue forms a tubular structure with its aromatic systems directed parallel to the axis of propagation, which creates a cavity with the potential to function as a host molecule. The synthetic strategy reported, based on a series of repeating Friedländer condensations that utilize pyrido[3,2-d]pyrimidine moieties as protected amino aldehydes, allows for the facile access of higher generations of helical, tubular structures. As a result of the synthetic strategy, only a helical isomer of the pentamer is possible. The structure and absolute configuration of the pentamer were elucidated from a combination of NMR spectroscopic data, optical properties, X-ray structures, and by comparison of an experimental electronic circular dichroism spectrum to a calculated spectrum.

A pair of molecular tweezers (syn-4) that consists of quinoline and pyrazine units fused to a bicyclic framework is presented. The tweezers were synthesised both as a racemic mixture (rac-4) and an enantiomerically pure form ((R,R,R,R)-4) starting from either racemic or enantiomerically pure bicyclo[3.3.1]nonane-2,6-dione (3). Homochiral dimers were observed in the solid state for rac-4. The self-association of both rac-4 and (R,R,R,R)-4 was studied in solution. A weak self-association constant in CDCl(3) was estimated by (1)H NMR spectroscopic dilution titration experiments in both cases, following several proton resonances. For this purpose, a general normalisation model for the accurate determination of association constants from multiple datasets was developed. In contrast to the solid state, no diastereomeric discrimination was observed for rac-4 in solution.

Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate–containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II–binding antibiotics, makes THCz promising scaffolds for development of cell wall–targeting antimicrobials.

The first generation of an organic nanotube based on the enantiomerically pure bicyclo[3.3.1]nonane framework is presented. The helical tube synthesised is the longest to date having its aromatic systems oriented parallel to the axis of propagation (length ∼26 Å and inner diameter ∼11 Å according to molecular dynamics simulations in chloroform). The synthesis of the tube, a heptamer, is based on a series of Friedländer condensations and the use of pyrido[3,2-d]pyrimidine units as masked 2-amino aldehydes, as a general means to propagate organic tubular structures and the introduction of a methoxy group for modification toward solubility and functionalization are described. The electronic CD spectra of the tube and molecular intermediates are correlated with theoretical spectra calculated with time-dependent density functional theory to characterize the chirality of the tube. Both experimental (NMR-titrations) and theoretical (molecular dynamics simulations) techniques are used to investigate the use of the tube as a receptor for the acetylcholine and guanidinium cations, respectively.

No abstract

A double conformationally restricted kinetically labile supramolecular catalytic system, the third generation, was designed and synthesized. We investigated the substrate selectivity of this system by performing competitive pairwise epoxidations of pyridyl‐ and phenyl‐appended olefins. We compared the obtained substrate selectivities to previous less preorganized generations of this system. Five different substrate pairs were investigated, and the present double conformationally restricted system showed higher normalized substrate selectivities (pyridyl versus phenyl) for two of the substrate pairs than the previous less conformationally restricted generations. As for the preorganization of the components of the system, the catalyst, and the receptor part, it was shown that for each substrate pair there was one generation that was better than the other to generate substrate‐selective catalysis.