The mar regulon: multiple resistance to antibiotics and other toxic ...

R EVIEWSresistance 31 . Inducible resistance had been suggestedby earlier studies that described chloramphenicol andtetracycline resistance in certain H. influenzae isolatesonly after prior contact with tetracycline 41 .Most first-step mar mutants that are resistant tolow levels of several antibiotics are still treatablewithin a clinical setting. However, for other first-stepmar mutants, clinical resistance to some antibiotics,namely tetracycline and rifampicin, is readily achieved 10 .Moreover, mar mutants synergistically enhance theresistance mediated by plasmids, for example, tetracyclineon plasmid R222 (S.B. Levy, unpublished).Bacteria in which the mar locus is constitutively expressedare protected from the bactericidal effects ofthe fluoroquinolones 11 and mutate more easily toconfer resistance to a higher fluoroquinolone concentration[Ref. 42; V. Hullen et al. (1998) 38thInternational Conference on Antimicrobial Agentsand Chemotherapy, San Diego, CA, USA, Abstr.C-187]. Certain clinical isolates of fluoroquinoloneresistantE. coli are mar mutants 43,44 and the marlocus contributes to the resistance phenotype 43,44 .Control of mar expression: possible therapeuticsOne strategy for controlling mar expression would beusing rational drug design. In theory, it should bepossible to design a new antibiotic(s) that interfereswith the functioning of MarA, its homologs or thegenetic loci (e.g. acrAB) regulated by this protein.Alternatively, White et al. 45 have demonstrated thefeasibility of using mar antisense DNA analogs toincrease the sensitivities of E. coli mar mutants toantibiotics. These synthetic oligonucleotides not onlydecrease the expression of a marORA lacZ fusion butare able to restore the bactericidal activity of norfloxacin,a fluoroquinolone, in a constitutive marmutant 45 .From what is now known about the control of margene expression in E. coli, the idea that a single mutationthat results in overexpression of a transcriptionalactivator (MarA) can reduce antibiotic susceptibilityis important to consider. It is anticipated thatthese mechanisms might undermine treatment andserve to thwart chemotherapy. Evidence for a role ofthe E. coli mar locus as an important stepping stonetowards clinically significant levels of resistance, resultingfrom mutations elsewhere on the chromosome,has begun to emerge. Nevertheless, its fundamentalrole could still be to ensure survival of its host undernaturally stressful conditions.AcknowledgementsWe thank L.M. McMurry for critical reading of the manuscript. 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