Designed to penetrate: Time-resolved interaction of single antibiotic molecules with bacterial pores
- *Laboratory of Physical and Structural Biology, National Institute of Child Health and Human Development, National Institutes of Health, Building 9, Room 1E-122, Bethesda, MD 20892-0924; †Institut Pharmacologie et Biologie Structurale, 31 077 Toulouse, France; and ‡St. Petersburg Nuclear Physics Institute, Gatchina 188350, Russia
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Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA, and approved May 28, 2002 (received for review April 3, 2002)
Abstract
Membrane permeability barriers are among the factors contributing to the intrinsic resistance of bacteria to antibiotics. We have been able to resolve single ampicillin molecules moving through a channel of the general bacterial porin, OmpF (outer membrane protein F), believed to be the principal pathway for the β-lactam antibiotics. With ion channel reconstitution and high-resolution conductance recording, we find that ampicillin and several other efficient penicillins and cephalosporins strongly interact with the residues of the constriction zone of the OmpF channel. Therefore, we hypothesize that, in analogy to substrate-specific channels that evolved to bind certain metabolite molecules, antibiotics have “evolved” to be channel-specific. Molecular modeling suggests that the charge distribution of the ampicillin molecule complements the charge distribution at the narrowest part of the bacterial porin. Interaction of these charges creates a region of attraction inside the channel that facilitates drug translocation through the constriction zone and results in higher permeability rates.
Footnotes
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↵ § To whom reprint requests should be addressed. E-mail: bezrukov{at}helix.nih.gov.
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This paper was submitted directly (Track II) to the PNAS office.
- Copyright © 2002, The National Academy of Sciences
