KatG catalase deficiency confers bedaquiline hyper-susceptibility to isoniazid resistant Mycobacterium tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) is a growing source of global mortality and threatens global control of tuberculosis (TB) disease. The diarylquinoline bedaquiline (BDQ) recently emerged as a highly efficacious drug against MDR-TB, defined as resistance to the first-line drugs isoniazid (INH) and rifampin. INH resistance is primarily caused by loss-of-function mutations in the catalase KatG, but mechanisms underlying BDQ's efficacy against MDR-TB remain unknown. Here we employ a systems biology approach to investigate BDQ hyper-susceptibility in INH-resistant Mycobacterium tuberculosis . We found hyper-susceptibility to BDQ in INH-resistant cells is due to several physiological changes induced by KatG deficiency, including increased susceptibility to reactive oxygen species and DNA damage, remodeling of transcriptional programs, and metabolic repression of folate biosynthesis. We demonstrate BDQ hyper-susceptibility is common in INH-resistant clinical isolates. Collectively, these results highlight how altered bacterial physiology can impact drug efficacy in drug-resistant bacteria.

Mobile genes in the human microbiome are structured from global to individual scales.

Recent work has underscored the importance of the microbiome in human health, and has largely attributed differences in phenotype to differences in the species present among individuals. However, mobile genes can confer profoundly different phenotypes on different strains of the same species. Little is known about the function and distribution of mobile genes in the human microbiome, and in particular whether the gene pool is globally homogenous or constrained by human population structure. Here, we investigate this question by comparing the mobile genes found in the microbiomes of 81 metropolitan North Americans with those of 172 agrarian Fiji islanders using a combination of single-cell genomics and metagenomics. We find large differences in mobile gene content between the Fijian and North American microbiomes, with functional variation that mirrors known dietary differences such as the excess of plant-based starch degradation genes found in Fijian individuals. Notably, we also observed differences between the mobile gene pools of neighbouring Fijian villages, even though microbiome composition across villages is similar. Finally, we observe high rates of recombination leading to individual-specific mobile elements, suggesting that the abundance of some genes may reflect environmental selection rather than dispersal limitation. Together, these data support the hypothesis that human activities and behaviours provide selective pressures that shape mobile gene pools, and that acquisition of mobile genes is important for colonizing specific human populations.

Self-encapsulation of poly-2,7-fluorenes in a dendrimer matrix.

The synthesis and characterization of complex dendritic, rigid rod poly-2,7-fluorene homopolymers and copolymers via a macromonomer approach is reported. Several 2,7-dibromofluorene monomers containing benzyl ether dendrons (generations 1, 2, and 3) in the 9,9'-position of the fluorene ring were prepared and employed in condensation polymerizations to yield both homopolymers and copolymers with diethylhexylfluorene. Fluorescence measurements of the materials reveal extensive conjugation along the polymer backbone. The determination of the solid-state PL spectra and quantum efficiencies showed that there is an apparent optimum size of the dendritic side groups with the [G-2]-derivatives showing high reactivity with associated site isolation of the conjugated chain. AFM analysis and DSC results confirmed that the hybrid polymers and copolymers did not show any sign of a microphase-separated morphology. First EL-results demonstrated that the homopolymers have higher turn-on voltages then the corresponding copolymers.

FTIR studies of intermolecular hydrogen bonding in halogenated ethanols.

The effect of halogen substitution on intermolecular hydrogen-bonding in ethanol is studied. Specifically, Fourier-transform infrared (FTIR) spectra of ethanol, 2,2,2-trifluoroethanol (TFE), and 2,2,2-trichloroethanol dissolved in carbon tetrachloride are reported as a function of temperature and concentration. The spectral intensities corresponding to monomer, dimer, and multimer formation are used to determine the effect of halogen substitution on intermolecular hydrogen-bonding. The enthalpy for dimerization was found to evolve from -4.2+/-0.3 kcal/mol in ethanol to -6.8+/-1.0 kcal/mol in TFE. An opposite trend was observed for multimer formation with enthalpies of -3.7+/-0.5 in ethanol and -2.1+/-1.4 kcal/mol in TFE. The majority of this evolution is assigned to the ability of ethanols to form intramolecular hydrogen bonds involving the hydoxyl proton and the halogen substituents.