BAL19403 is a macrolide antibiotic from a novel structural class with potent activity against propionibacteria in vitro. The antibacterial spectrum of BAL19403 covers clinical isolates with mutations in the 2057 to 2059 region of 23S rRNA that confer resistance to erythromycin and clindamycin. The basis of this improved activity was investigated by ribosome binding assays and by a coupled transcription and translation assay. The latter was specifically developed for the use of ribosomes from Propionibacterium acnes. BAL19403 inhibited protein expression by ribosomes from erythromycin-sensitive and erythromycin-resistant P. acnes with similar potencies if the resistance was due to G2057A or A2058G mutations. BAL19403 showed a >10-fold higher activity than erythromycin against ribosomes from a strain with the erm(X) gene. Erm(X) confers high levels of macrolide and lincosamide resistance by dimethylation of A2058. Assays with such ribosomes showed that BAL19403 was potent enough to inhibit half of the total activity with a 50% inhibitory concentration very close to the value measured with erythromycin-sensitive ribosomes. We concluded from our data that the P. acnes strain with the erm(X) gene had a mixed population of ribosomes, with macrolide-sensitive and macrolideresistant species.Propionibacterium acnes is a skin-colonizing gram-positive bacterium associated with sebum-excreting pilosebaceous follicles (20,23,24). P. acnes is involved in the development of inflamed lesions in the course of acne (3). The observed inflammatory response is presumably directed against propionibacterial antigens (15,18,35). Mild to moderate inflammatory acne is often treated with antibiotics, usually erythromycin (ERY) or clindamycin (CLI), but sometimes with tetracycline (34). Antibiotic treatment of acne is nowadays challenged by an increasing incidence of antibiotic-resistant P. acnes (5,11,19,32). A worldwide survey revealed that about 50% of clinical P. acnes isolates were resistant to ERY (Ery R ) and about 20% were resistant to tetracycline (11). Apart from playing a role in acne, propionibacteria can also be the main pathogen in severe infections, especially after surgery or in immune-compromised patients. A survey covering 13 European countries revealed that 15.1% of P. acnes clinical isolates from different systemic infections were resistant to CLI (Cli R ) and 17.1% were Ery R (27). Macrolide antibiotics interact with the 50S ribosomal subunit and block bacterial translation. Several mechanisms, including target alteration, are known for conferring macrolide resistance. Mutations of G2057, A2058, and A2059 (Escherichia coli numbering) in domain V of the 23S rRNA are the most frequently encountered mechanisms in P. acnes (26,30,31,33). Mutations of G2057 reportedly cause low levels of ERY resistance in P. acnes (MICs of 1 to 2 g/ml), whereas mutations of A2058 or A2059 lead to high-level ERY resistance, with MICs of Ͼ128 g/ml (29-31). The expression of the Erm(X) methylase leads to dimethylation of A2058, resulting in hi...
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