Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective.

INTRODUCTION: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed. Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concentration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy.

Synthesis and biological evaluation of selective and potent cyclin-dependent kinase inhibitors.

A new series of 2,6,9-trisubstituted purines, structurally related to the cyclin-dependent kinase (CDK) inhibitor Roscovitine, has been synthesized. These compounds mainly differ by the substituent on the C-2 position which encompasses a diol group. These compounds were screened for kinase inhibitory activities and antiproliferative effects. They were shown to be potent inhibitors of cyclin-dependent kinases but also, for some of them of casein kinase 1 (CK1) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). The inhibition of kinases was accompanied by an antiproliferative effect against several tumor cell-lines. The most potent derivatives inhibited SH-SY5Y (neuroblastoma) tumor cell line with an IC(50) < 0.5 µM which means approximately a 30 fold increase compared to Roscovitine. A valine ester was also prepared from the most potent inhibitor to serve as a prodrug.