Reducing antibiotic resistance

Schrag, Stephanie J.; Perrot, Véronique

doi:10.1038/381120b0

Cited by 227 publications

(173 citation statements)

References 9 publications

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“…There are many medically and ecologically relevant examples of pathogen evolution, such as the emergence of drug-resistant strains (Schrag & Perrot, 1996) and the decreased virulence of introduced control agents (Fenner, 1983). Host-pathogen systems are typically not well mixed, but rather are spatially distributed.…”

Section: Introductionmentioning

confidence: 99%

Dynamics and Genealogy of Strains in Spatially Extended Host–Pathogen Models

Rauch

Sayama

Bar‐Yam

2003

Journal of Theoretical Biology

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Section: Introductionmentioning

confidence: 99%

Dynamics and Genealogy of Strains in Spatially Extended Host–Pathogen Models

Rauch

Sayama

Bar‐Yam

2003

Journal of Theoretical Biology

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“…Lenski (1988) demonstrated large ¢tness costs of mutations which confer the resistance of Escherichia coli to the virus T4, but after 400 generations in the absence of T4, these costs were much reduced even though resistance remained. Several experiments with bacteria have shown that CA can quickly overcome the pleiotropic costs which arise from resistance to various antibiotics (Bouma & Lenski 1988;Cohan et al 1994;Schrag & Perrot 1996;Schrag et al 1997;BjÎrkman et al 1998; for a review, see Lenski 1998). In a recent study which did not involve any resistance mutations, Burch & Chao (1999) found that one particular deleterious mutation in an RNA virus could be compensated for to varying degrees by several di¡erent mutations.…”

Section: Introductionmentioning

confidence: 99%

Pervasive compensatory adaptation inEscherichia coli

Moore

Rozen

Lenski

2000

Proc. R. Soc. Lond. B

127

115

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To investigate compensatory adaptation (CA), we used genotypes of Escherichia coli which were identical except for one or two deleterious mutations. We compared CA for (i) deleterious mutations with large versus small e¡ects, (ii) genotypes carrying one versus two mutations, and (iii) pairs of deleterious mutations which interact in a multiplicative versus synergistic fashion. In all, we studied 14 di¡erent genotypes, plus a control strain which was not mutated. Most genotypes showed CA during 200 generations of experimental evolution, where we de¢ne CA as a ¢tness increase which is disproportionately large relative to that in evolving control lines, coupled with retention of the original deleterious mutation(s). We observed greater CA for mutations of large e¡ect than for those of small e¡ect, which can be explained by the greater bene¢t to recovery in severely handicapped genotypes given the dynamics of selection. The rates of CA were similar for double and single mutants whose initial ¢tnesses were approximately equal. CA was faster for synergistic than for multiplicative pairs, presumably because the marginal gain which results from CA for one of the component mutations is greater in that case. The most surprising result in our view, is that compensation should be so readily achieved in an organism which is haploid and has little genetic redundancy. This ¢nding suggests a degree of versatility in the E. coli genome which demands further study from both genetic and physiological perspectives.

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“…For example, it has been shown in Escherichia coli that carriage of resistance genes on a plasmid is associated with a decreased growth rate, and that these strains can accumulate chromosomal compensatory mutations that, by an unknown mechanism, compensate for the growth rate decrease (2,3). Likewise, it has been shown that slow-growing streptomycin-resistant mutants of E. coli can accumulate compensatory mutations that restore rapid growth under laboratory conditions without affecting the resistance (4). Interestingly, these compensatory mutations appear to create a genetic background in which the streptomycinsensitive revertants have a strong selective disadvantage, implying that it would be difficult for an evolved resistant strain to become sensitive even in the absence of the antibiotic (5).…”

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confidence: 99%

Virulence of antibiotic-resistant Salmonella typhimurium

Björkman

Hughes

Andersson

1998

Proc. Natl. Acad. Sci. U.S.A.

318

230

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We show that most Salmonella typhimurium mutants resistant to streptomycin, rifampicin, and nalidixic acid are avirulent in mice. Of seven resistant mutants examined, six were avirulent and one was similar to the wild type in competition experiments in mice. The avirulent-resistant mutants rapidly accumulated various types of compensatory mutations that restored virulence without concomitant loss of resistance. Such second-site compensatory mutations were more common then reversion to the sensitive wild type. We infer from these results that a reduction in the use of antibiotics might not result in the disappearance of the resistant bacteria already present in human and environmental reservoirs. Thus, second-site compensatory mutations could increase the fitness of resistant bacteria and allow them to persist and compete successfully with sensitive strains even in an antibiotic-free environment.During the last decade there has been an alarming increase in the appearance of antibiotic-resistant bacteria as a result of an increased use of antibiotics combined with the exceptional ability of bacteria to develop resistance. One strategy to reverse this development is to decrease the use of antibiotics to promote the disappearance of the resistant bacteria present in human and environmental reservoirs. Implicit in this reasoning is that resistance confers a cost on the bacteria, which results in a counter-selection against resistant strains in an antibiotic-free environment. An associated question and potential problem is whether the supposedly less fit, avirulentresistant bacteria might accumulate compensatory mutations that restore fitness and virulence without loss of resistance, and thereby stabilize the resistant population.In spite of the importance of these questions, there are few experiments that explicitly address them under the relevant conditions, i.e., in animal model systems using genetically defined bacterial strains (for a review, see ref. 1). For example, it has been shown in Escherichia coli that carriage of resistance genes on a plasmid is associated with a decreased growth rate, and that these strains can accumulate chromosomal compensatory mutations that, by an unknown mechanism, compensate for the growth rate decrease (2, 3). Likewise, it has been shown that slow-growing streptomycin-resistant mutants of E. coli can accumulate compensatory mutations that restore rapid growth under laboratory conditions without affecting the resistance (4). Interestingly, these compensatory mutations appear to create a genetic background in which the streptomycinsensitive revertants have a strong selective disadvantage, implying that it would be difficult for an evolved resistant strain to become sensitive even in the absence of the antibiotic (5). There are also animal data which indicate that tetracyclineresistant E. coli persist in pigs long after the antibiotic has been removed, suggesting that the added burden of this particular resistance in vivo is in fact small (6). Finally, studies of human clini...

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Reducing antibiotic resistance

Cited by 227 publications

References 9 publications

Dynamics and Genealogy of Strains in Spatially Extended Host–Pathogen Models

Dynamics and Genealogy of Strains in Spatially Extended Host–Pathogen Models

Pervasive compensatory adaptation inEscherichia coli

Virulence of antibiotic-resistant Salmonella typhimurium

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