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Antimicrobial Agents and Chemotherapy, June 2000, p. 1562-1567, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Studies of the Novel Ketolide ABT-773: Transport, Binding to Ribosomes, and Inhibition of Protein Synthesis in Streptococcus pneumoniae

John O. Capobianco, ZhenSheng Cao, Virginia D. Shortridge, ZhenKun Ma, Robert K. Flamm, and Ping Zhong*

Infectious Disease Research, Abbott Laboratories, Abbott Park, Illinois 60064

Received 1 November 1999/Returned for modification 2 February 2000/Accepted 12 March 2000

Macrolide resistance in Streptococcus pneumoniae has been associated with two main mechanisms: target modification by Erm methyltransferases and efflux by macrolide pumps. The ketolide ABT-773, which has a 3-keto group and no L-cladinose sugar, represents a new class of drugs with in vitro activity against a variety of resistant bacteria. Several approaches were undertaken to understand how ABT-773 was able to defeat resistance mechanisms. We demonstrated tighter ribosome binding of ABT-773 than erythromycin. We also showed that ABT-773 (i) accumulated in macrolide-sensitive S. pneumoniae at a higher rate than erythromycin, (ii) was able to bind with methylated ribosomes, though at lower affinities than with wild-type ribosomes, and (iii) accumulated in S. pneumoniae strains with the efflux-resistant phenotype.

* Corresponding author. Mailing address: D-47P, AP52-1N, Abbott Laboratories, 200 Abbott Park Rd., Abbott Park, IL 60064-6217. Phone: (847) 937-0500. Fax: (847) 938-3403. E-mail: Ping.Zhong{at}abbott.com.

Antimicrobial Agents and Chemotherapy, June 2000, p. 1562-1567, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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