Genetic basis of resistance in Propionibacterium acnes strains isolated from diverse types of infection in different European countries

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Comparative In Vitro Activities of Retapamulin (SB-275833) against 141 Clinical Isolates of Propionibacterium spp., Including 117 P. acnes Isolates

Goldstein

Citron²,

Merriam³

et al. 2006

“…Additional testing confirmed that this GE2270A derivative retains activity against several independent clindamycin-and erythromycin-resistant P. acnes clinical isolates (D. Jabes, unpublished data). This observation is not surprising, since clindamycin and erythromycin resistance in P. acnes mostly involves mutation in 23S RNA (27)(28)(29), a site unrelated to the interaction of EF-Tu with the ribosome. Antibacterial agents with an extremely narrow spectrum hold the promise of curing infections with minimal disturbance of commensal flora.…”

Section: Discussionmentioning

confidence: 99%

A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes

Fabbretti

Gaspari³

et al. 2015

A 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 of Propionibacterium acnes and, to a lesser extent, against Enterococcus faecalis. Furthermore, NAI003 showed a time-and dose-dependent killing of both a clindamycin-resistant and a clindamycinsensitive P. acnes isolate. Gel shift experiments indicated that, like the parent compound, NAI003 retained the ability to bind to elongation factors Tu (EF-Tus) derived from Escherichia coli, E. faecalis, or P. acnes, albeit with reduced efficiency. In contrast, EF-Tus derived from the NAI003-insensitive Staphylococcus aureus or Streptococcus pyogenes did not bind this compound. These results were confirmed by in vitro studies using a hybrid translation system, which indicated that NAI003 can inhibit most efficiently protein synthesis driven by the P. acnes EF-Tu. P. acnes mutants resistant to NAI003 were isolated by direct plating. With one exception, all analyzed strains carried mutations in the tuf gene, encoding EF-Tu. Because of its selective effect on P. acnes in 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.

“…The expression of the Erm(X) methylase leads to dimethylation of A2058, resulting in high-level resistance to both ERY and CLI. The erm(X) gene was found in less than 10% of Ery R clinical isolates collected in different European countries (26,32).BAL19403, a new macrolide from our antibacterial research programs, was found to have pronounced activity against Ery R and Cli R propionibacteria and to possess good anti-inflammatory properties (16,17,22) (Fig. 1).…”

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Activity of the Novel Macrolide BAL19403 against Ribosomes from Erythromycin-Resistant Propionibacterium acnes

Dreier

Amantea

Kellenberger

et al. 2007

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...