A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes

Abstract

ABSTRACTA chemical derivative of the thiopeptide GE2270A, designated NAI003, was found to possess a substantially reduced antibacterial spectrum in comparison to the parent compound, being active against just a few Gram-positive bacteria. In particular, NAI003 retained low MICs against all tested isolates ofPropionibacterium acnesand, to a lesser extent, againstEnterococcus faecalis. Furthermore, NAI003 showed a time- and dose-dependent killing of both a clindamycin-resistant and a clindamycin-sensitiveP. acnesisolate. Gel shift experiments indicated that, like the parent compound, NAI003 retained the ability to bind to elongation factors Tu (EF-Tus) derived fromEscherichia coli,E. faecalis, orP. acnes, albeit with reduced efficiency. In contrast, EF-Tus derived from the NAI003-insensitiveStaphylococcus aureusorStreptococcus pyogenesdid not bind this compound. These results were confirmed byin vitrostudies using a hybrid translation system, which indicated that NAI003 can inhibit most efficiently protein synthesis driven by theP. acnesEF-Tu.P. acnesmutants resistant to NAI003 were isolated by direct plating. With one exception, all analyzed strains carried mutations in thetufgene, encoding EF-Tu. Because of its selective effect onP. acnesin comparison to resident skin flora, NAI003 represents a promising candidate for the topical treatment of acne, which has already completed a phase 1 clinical study.