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Targeting DnaN for tuberculosis therapy using novel griselimycins
Ist Teil von
Science (American Association for the Advancement of Science), 2015-06, Vol.348 (6239), p.1106-1112
Ort / Verlag
Washington: American Association for the Advancement of Science
Erscheinungsjahr
2015
Link zum Volltext
Quelle
American Association for the Advancement of Science
Beschreibungen/Notizen
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.