Multidrug evolutionary strategies to reverse antibiotic resistance

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Science  01 Jan 2016:
Vol. 351, Issue 6268, aad3292
DOI: 10.1126/science.aad3292

Evolving antibiotic rescue stratagems

Antibiotic resistance threatens to put modern medicine into reverse. But we are not at the end of our options for currently available drugs. Baym et al. review what can be done by using combinations of antibiotics to circumvent bacteria's evolutionary strategies. For instance, resistance to one drug may cause sensitivity to another, the effectiveness of two drugs can be synergized by a resistance mutation, and some negative drug interactions may even be beneficial in selecting against resistance. Although not simple to assess, drug combinations still have something to offer for the development of sorely needed anti-infectives.

Science, this issue p. 10.1126/science.aad3292

Structured Abstract


Antibiotics are among the most important tools in medicine, but their efficacy is threatened by the evolution of resistance. Since the earliest days of antibiotics, resistance has been observed and recognized as a threat; today, many first-generation drugs are all but ineffective. The paradox of antibiotics is that through their use, they not only inhibit an infection but also select for the emergence and spread of resistance, directly counteracting their long-term efficacy. We have thus far avoided a crisis through the continued modification of existing compounds and the discovery of new antibiotic classes. It has been hoped that restricting the use of particular antibiotics would neutralize the selective advantage of resistance and restore widespread sensitivity over time; however, decades of experience have shown that resistance does not disappear so easily. The same is true for combining antibiotics with compounds that inhibit their specific resistance mechanisms; this approach is effective in potentiating and broadening the spectrum of antibiotics, but it only neutralizes the advantage of resistant bacteria and does not actively select against resistance over time. To prevent the evolution of resistance or turn a resistant population susceptible again, we need ways to fully invert the selective advantage of resistance.


Recent discoveries have shown that it is possible to invert the selective advantage of resistant bacteria and reverse the evolution of antibiotic resistance. Whereas with single-drug therapy, there is always a selective advantage to resistance, specific combinations of drugs can inhibit bacterial growth while disfavoring resistance to the individual components. To confer a direct disadvantage to resistant mutants, techniques have been developed that exploit the specific physiological and evolutionary interactions between drugs. First, if one drug partially suppresses the effect of another, becoming resistant to the first drug will remove its protection against the second, giving a disadvantage to the resistant mutants. Second, mutations that confer resistance to a drug can be counteracted if they induce synergy between the drug and another compound. Finally, there can be trade-offs between resistances to different compounds such that resistance to one antibiotic causes collateral sensitivity to another antibiotic or to a compound whose toxicity is mediated by the resistance mechanism. These approaches can be used to invert the selective advantage of resistant bacteria competing with their sensitive cousins and can potentially decrease the rate at which resistance evolves, or even drive a resistant bacterial population back toward drug sensitivity.


Substantial barriers remain for the clinical application of selection-inverting treatment strategies. Antibiotic treatment decisions must typically be made within minutes, whereas the isolation and analysis of an infection take between hours and days, even with state-of-the art technology. Further, the optimal choice of these strategies depends on the specific genetics of the pathogen and the resistance mechanism. Thus, practical deployment of selection inversion approaches will require the development of fast, genomic diagnostics that can identify not only the pathogen’s current resistance profile but also its future potential for evolution of resistance. Such genomic diagnostics could further be used to inform treatment, channel pathogens toward less resistance-prone genotypes, monitor population-wide and environmental resistance levels, and identify new resistance mechanisms before they enter the clinic.

Additionally, most of the studies on selection inversion have been performed in vitro and need to be validated in animal models and clinical isolates. Strategies relying on coadministration are further complicated by pharmacokinetics, which may vary across compounds. Moreover, the unique drug interactions underlying these approaches may change across different environments and genetic backgrounds or over time as the pathogens evolve. Finally, the deployment of these strategies requires a careful ethical balance between curing the individual and reducing resistance in the community. Ultimately, combating resistance will necessitate a portfolio of strategies that anticipate the evolution of the infection and adapt to both treat and avoid resistance.

Countering antibiotic resistance through selection inversion.

Resistance to antibiotics evolves as a direct consequence of their use to suppress bacterial growth. The present strategy of discovering new antibiotics and waiting for new resistance to evolve is untenable in the long term. However, promising new strategies to manipulate evolution and invert selection against resistance may prolong the utility of existing antibiotics or even restore the activity of old drugs.


Antibiotic treatment has two conflicting effects: the desired, immediate effect of inhibiting bacterial growth and the undesired, long-term effect of promoting the evolution of resistance. Although these contrasting outcomes seem inextricably linked, recent work has revealed several ways by which antibiotics can be combined to inhibit bacterial growth while, counterintuitively, selecting against resistant mutants. Decoupling treatment efficacy from the risk of resistance can be achieved by exploiting specific interactions between drugs, and the ways in which resistance mutations to a given drug can modulate these interactions or increase the sensitivity of the bacteria to other compounds. Although their practical application requires much further development and validation, and relies on advances in genomic diagnostics, these discoveries suggest novel paradigms that may restrict or even reverse the evolution of resistance.

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