Vectorization efforts to increase Gram-negative intracellular drug concentration: a case study on HldE-K inhibitors.

In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin.

From triclosan toward the clinic: discovery of nonbiocidal, potent FabI inhibitors for the treatment of resistant bacteria.

In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.

Systematic synthesis of inhibitors of the two first enzymes of the bacterial heptose biosynthetic pathway: towards antivirulence molecules targeting lipopolysaccharide biosynthesis.

L-Heptoses (L-glycero-D-manno-heptopyranoses) are constituents of the inner core of lipolysaccharide (LPS), a molecule playing key roles in the mortality of many infectious diseases as well as in the virulence of many human pathogens. The inhibition of the first enzymes of the bacterial heptose biosynthetic pathway is an almost unexplored field to date although it appears to be a very novel way for the development of antivirulence drugs. We report the synthesis of a series of D-glycero-D-manno-heptopyranose 7-phosphate (H7P) analogues and their inhibition properties against the isomerase GmhA and the the kinase HldE, the two first enzymes of the bacterial heptose biosynthetic pathway.

Towards Gram-positive antivirulence drugs: new inhibitors of Streptococcus agalactiae Stk1.

A structure-activity relationship study from a screening hit and structure-based design strategy has led to the identification of bisarylureas as potent inhibitors of Streptococcus agalactiae Stk1. As this target has been directly linked to bacterial virulence, these inhibitors can be considered as a promising step towards antivirulence drugs.