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Antimicrobial Agents and Chemotherapy, June 2002, p. 1680-1687, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1680-1687.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mefloquine and New Related Compounds Target the F0 Complex of the F0F1 H+-ATPase of Streptococcus pneumoniae

Antonio Javier Martín-Galiano,1 Begoña Gorgojo,1 Calvin M. Kunin,2 and Adela G. de la Campa1*

Unidad de Genética Bacteriana (Consejo Superior de Investigaciones Científicas), Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain,1 Department of Internal Medicine, The Ohio State University, Columbus, Ohio2

Received 26 November 2001/ Returned for modification 7 February 2002/ Accepted 26 February 2002

The activities of mefloquine (MFL) and related compounds against previously characterized Streptococcus pneumoniae strains carrying defined amino acid substitutions in the c subunit of the F0F1 H+-ATPase were studied. In addition, a series of MFL-resistant (Mflr) strains were isolated and characterized. A good correlation was observed between inhibition of growth and inhibition of the membrane-associated F0F1 H+-ATPase activity. MFL was about 10-fold more active than optochin and about 200-fold more active than quinine in inhibiting both the growth and the ATPase activities of laboratory pneumococcal strain R6. Mutant strains were inhibited by the different compounds to different degrees, depending on their specific mutations in the c subunit. The resistant strains studied had point mutations that changed amino acid residues in either the c subunit or the a subunit of the F0 complex. Changes in the c subunit were located in one of the two transmembrane {alpha} helices: residues M13, G14, G20, M23, and N24 of helix 1 and residues M44, G47, V48, A49, and V57 of helix 2. Changes in the a subunit were also found in either of the transmembrane {alpha} helices, helix 5 or 6: residue L186 of helix 5 and residues W206, F209, and S214 of helix 6. These results suggest that the transmembrane helices of the c and a subunits interact and that the mutated residues are important for the structure of the F0 complex and proton translocation.

* Corresponding author. Mailing address: Unidad de Genética Bacteriana (Consejo Superior de Investigaciones Científicas), Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain Phone: (341) 509-7904. Fax: (341) 509-7919. E-mail: agcampa{at}isciii.es.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1680-1687, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1680-1687.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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