Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

The cell cycle of pathogenic fungi: target for drugs.

Life-threatening fungal infections are becoming more frequent and involve a greater variety of strains, many of which are drug-resistant. Both public research organisations and the pharmaceutical industry are committed to the development of new drugs to satisfy this increasing medical need. The approach described here exemplifies the efforts directed towards the discovery of drugs which are active against novel targets, exemplified by the cell-cycle regulator, Civ1.