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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.