Antibiotic interactions that select against resistance

Nature. 2007 Apr 5;446(7136):668-71.

Antibiotic interactions that select against resistance.
Chait R, Craney A, Kishony R.

Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.

Multidrug combinations are increasingly important in combating the spread of antibiotic-resistance in bacterial pathogens. On a broader scale, such combinations are also important in understanding microbial ecology and evolution. Although the effects of multidrug combinations on bacterial growth have been studied extensively, relatively little is known about their impact on the differential selection between sensitive and resistant bacterial populations. Normally, the presence of a drug confers an advantage on its resistant mutants in competition with the sensitive wild-type population. Here we show, by using a direct competition assay between doxycycline-resistant and doxycycline-sensitive Escherichia coli, that this differential selection can be inverted in a hyper-antagonistic class of drug combinations. Used in such a combination, a drug can render the combined treatment selective against the drug's own resistance allele. Further, this inversion of sele ction seems largely insensitive to the underlying resistance mechanism and occurs, at sublethal concentrations, while maintaining inhibition of the wild type. These seemingly paradoxical results can be rationalized in terms of a simple geometric argument. Our findings demonstrate a previously unappreciated feature of the fitness landscape for the evolution of resistance and point to a trade-off between the effect of drug interactions on absolute potency and the relative competitive selection that they impose on emerging resistant populations.

PMID: 17410176 [PubMed - indexed for MEDLINE]

Comments

This page was submitted by a member, so I am just updating the physician pages by adding it. It is a great bit of information for the MDwho is concerned about causing resistance as it affirms that combination protocols are a safer approach.
marie
On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5. Currently on: Doxy 200, Azith 3x week, Tini cont. since April '07, all supplementsi.
"Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

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