Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.

The increasing resistance to antibacterials commonly employed in the clinic and the growth of multidrug resistant strains suggest that the development of new therapeutic approaches should be of primary concern. In this context, EPIs may restore life to old drugs. In the present work, the EPI activity of the COX-2 inhibitor celecoxib was confirmed and a new class of pyrazolo­[4,3-c]­[1,2]­benzothiazine 5,5-dioxide analogues acting as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump was identified.

The thiopyranopyridine moiety was synthesized as a new heterocyclic base to be inserted at the C-7 position of selected quinolone nuclei followed by a determination of antibacterial activity against strains of Staphylococcus aureus. Selected thiopyranopyridinylquinolones showed significant antimicrobial activity, including strains having mutations in gyrA and grlA as well as other strains overexpressing the NorA multidrug (MDR) efflux pump. Most derivatives did not appear to be NorA substrates. The effect of the thiopyranopyridinyl substituent on making these quinolones poor substrates for NorA was investigated further. Several quinolone ester intermediates, devoid of any intrinsic antibacterial activity, were tested for their abilities to inhibit the activities of NorA (MFS family) and MepA (MATE family) S. aureus MDR efflux pumps. Selected quinolone esters were capable of inhibiting both MDR pumps more efficiently than the reference compound reserpine. Moreover, they also were able to restore, and even enhance, the activity of ciprofloxacin toward some genetically modified resistant S. aureus strains.

Chiral systems may exhibit auxetic behavior, i.e. they may have a negative Poisson's ratio. This particular property has led to their being studied extensively by several authors. A Finite Elements Study is presented here, investigating the mode of connection between the nodes and ligaments in the anti‐tetrachiral structure. The results show that the amount of gluing material used to attach the ligaments to the node will not affect the Poisson's ratio, but may have a large influence on the observed stiffness of the structure (Young's modulus). It is also shown that the stiffness of the glue will have a large effect on the mode of deformation of the chiral system. This change in mechanism was found to effect the stiffness of the structure but not its Poisson's ratios.

Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while seven compounds inhibited only NorA. These results demonstrate that Pgp and NorA inhibitors do not necessarily overlap, opening the way to safer therapeutic use of effective NorA inhibitors.

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Using experimental data, it is shown that the Poisson's ratios of standard (untreated) open cell polyurethane foam vary when loading in different loading directions, since foam is inherently asymmetric and anisotropic. The loading direction which is in plane orthogonal to the rise direction of the foam constantly exhibited the most negative Poisson's ratio across foam samples of different types, even at moderate compressive strains. It was also shown that although the foam may become auxetic at very high values of compressive strain, it shows an incremental negative Poisson's ratio at moderate compressive strains. The results obtained are discussed in light of the deformation mechanisms, which have been proposed in literature to explain negative Poisson's ratios in foams. The effects of changing loading direction on the mechanical response of the foam are highlighted. An image of the symmetrical face of a foam cube, taken using a confocal microscope at 4× magnification.