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Anti-adhesion therapy of bacterial diseases: prospects and problemsIntroductionReceptor analogs as anti-adhesive agentsAdhesin analogs as anti-adhesive agentsDietary inhibitors of adhesionSublethal concentrations of antibioticsAdhesin-based vaccinesHost-derived anti-adhesins in innate immunityConcluding remarksAcknowledgementsReferencesMiniReviewAnti-adhesion therapy of bacterial diseases: prospects and problemsItzhak Ofeka; , David L. Hastyb;c, Nathan SharondaDepartment of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelbDepartment of Anatomy and Neurobiology, University of Tennessee, Memphis, TN 38163, USAcResearch Service (151), VA Medical Center, Memphis, TN 38104, USAdDepartment of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, IsraelReceived 5 May 2003; received in revised form 17 July 2003; accepted 17 July 2003First published online 1 September 2003AbstractThe alarming increase in drug-resistant bacteria makes a search for novel means of fighting bacterial infections imperative. Anattractive approach is the use of agents that interfere with the ability of the bacteria to adhere to tissues of the host, since such adhesion isone of the initial stages of the infectious process. The validity of this approach has been unequivocally demonstrated in experimentsperformed in a wide variety of animals, from mice to monkeys, and recently also in humans. Here we review various approaches to anti-adhesion therapy, including the use of receptor and adhesin analogs, dietary constituents, sublethal concentrations of antibiotics andadhesin-based vaccines. Because anti-adhesive agents are not bactericidal, the propagation and spread of resistant strains is much lesslikely to occur than as a result of exposure to bactericidal agents, such as antibiotics. Anti-adhesive drugs, once developed, may, therefore,serve as a new means to fight infectious diseases.3 2003 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. Keywords: Cranberry; Carbohydrate; Fimbria1. IntroductionAnti-adhesion therapy and anti-adhesin immunity aremeant to reduce contact between host tissues and patho-gens, either by prevention or reversal of adhesion of theinfectious agent. It is well established that adhesion ofenteric, oral and respiratory bacteria is required for colo-nization and for subsequent development of disease [1].Moreover, bacteria assume a signi¢cantly greater resis-tance to clearance by normal cleansing mechanisms andto killing by normal immune factors, bacteriolytic enzymesand antibiotics when they are adherent to surfaces. Suchbacteria are better able to acquire nutrients, further en-hancing their ability to survive and infect the host [2].Thus, the adherent state is advantageous for bacterial sur-vival and a key step in pathogenesis. Therefore, preventionof adhesion at an early stage following the exposure of thehost to pathogens should prevent the disease.Bacteria can adapt to many noxious or deleteriousagents, either by mutation, by acquisition of new geneticmaterial via horizontal transfer or by phenotypic variation[1]. Bacteria resistant to anti-adhesion agents may also beexpected to emerge, but because these agents do not act bykilling or arresting growth of the pathogen, as, for exam-ple, antibiotics do, it is reasonable to assume that strainsresistant to anti-adhesion agents will be diluted with thesensitive bacteria whose adhesion is inhibited and are shedout of the host (Fig. 1). It follows that spread of bacteriaresistant to the anti-adhesion agent is expected to occur atsigni¢cantly lower frequencies than that of bacteria resis-tant to antibiotics. This would potentially allow sensitiveand resistant organisms to propagate and be transmittedat equivalent rates, dramatically slowing the emergence ofa predominantly resistant population.The major drawback of anti-adhesion therapy is thatmost pathogens possess genes encoding for more thanone type of adhesin, so that during the infectious processthe population of pathogens may express more than oneof these adhesins. Adhesion may also involve factors otherthan just adhesin^receptor interactions such as hydropho-bic and other non-speci¢c interactions under di¡erent0928-8244 / 03 / $22.00 3 2003 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.doi:10.1016/S0928-8244(03)00228-1* Corresponding author. Tel.: +972 (3) 6409 059;Fax: +972 (3) 6409 160.E-mail address: [email protected] (I. Ofek). FEMSIM 1609 18-9-03FEMS Immunology and Medical Microbiology 38 (2003) 181^191www.fems-microbiology.orgshear-forces. For anti-adhesion therapy to be e¡ective, itwill probably be necessary to use multiple agents speci¢-cally inhibiting each type of adhesin of the infectingpathogen or a single agent that exhibits a broad spectrumof anti-adhesion activity. For earlier discussions of anti-adhesion therapy see [2^5].2. Receptor analogs as anti-adhesive agentsThere is evidence that receptor analogs as agents foranti-adhesion therapy would be practical primarily againstpathogens that bind to animal cells via carbohydrate-spe-ci¢c adhesins (i.e. lectins). In these cases, the receptor ana-logs are saccharides that are structurally similar to thoseof the glycoprotein or glycolipid receptors for the adhesinand, therefore, act by competitive inhibition. It was lessthan three decades ago that mannose was ¢rst shown to bea receptor for enterobacteria [6]. Since then, the sugarspeci¢cities of many bacteria have been determined, lead-ing to the development of receptor-like carbohydrates,which inhibit the adhesion of pathogens to host cellsand tissues [1]. The concentrations of the carbohydratesrequired for e¡ective inhibition of adhesion in vitro areusually high, in the millimolar range, because the a⁄nityof the saccharides for the bacterial lectins is low. It can beincreased several orders of magnitude by covalently link-ing a hydrophobic residue such as phenyl or methyl um-belliferyl to the saccharide [7]. A⁄nity can be similarlyincreased by attaching many copies of the saccharide toa suitable carrier, yielding multivalent adhesin inhibitors,as demonstrated for Helicobacter pylori [8,9] and for type1 ¢mbriated Escherichia coli [10].The feasibility of using saccharides to protect againstexperimental infections by bacteria expressing adhesivelectins was ¢rst demonstrated more than two decadesago


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