Accelerated evolution of resistance in multidrug environments.
The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions--synergy or antagonism--between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds of Escherichia coli populations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clinical settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.
Hegreness
Matthew
M
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Shoresh
Noam
N
Damian
Doris
D
Hartl
Daniel
D
Kishony
Roy
R
D000220:Adaptation, Biological; D005075:Biological Evolution; D018432:Drug Resistance, Multiple / Q000235:genetics*
J Antimicrob Chemother. 1983 Dec;12(6):555-63
6662835
Nature. 2007 Apr 5;446(7136):668-71
17410176
Antimicrob Agents Chemother. 1972 Dec;2(6):470-5
4596743
Science. 2006 Mar 17;311(5767):1615-7
16543462
Br Med J. 1952 May 31;1(4769):1162-8
14925408
Dis Chest. 1955 Sep;28(3):260-74
13251084
J Bacteriol. 1953 Apr;65(4):454-65
13069402
J Antimicrob Chemother. 2003 Jul;52(1):11-7
12805267
Pharmacol Rev. 1995 Jun;47(2):331-85
7568331
Annu Rev Med. 1954;5:1-26
13181367
Microbiol Mol Biol Rev. 2001 Jun;65(2):232-60 ; second page, table of contents
11381101
Lancet Infect Dis. 2005 Feb;5(2):115-9
15680781
Trends Microbiol. 1997 Jun;5(6):234-40
9211644
Clin Infect Dis. 2005 Jul 15;41(2):149-58
15983909
Antimicrob Agents Chemother. 1976 Nov;10(5):802-8
795370
Antimicrob Agents Chemother. 2007 Jun;51(6):2236-9
17404007
Nat Med. 2004 Dec;10(12 Suppl):S122-9
15577930
Nat Genet. 2008 May;40(5):676-81
18408719
Nature. 1978 Jan 26;271(5643):385-6
340962
Science. 2006 Apr 7;312(5770):111-4
16601193
Nat Rev Genet. 2003 Jun;4(6):457-69
12776215
Pharmacol Rev. 1989 Jun;41(2):93-141
2692037
J Bacteriol. 1953 Aug;66(2):150-8
13084551
Bull World Health Organ. 2002;80(2):126-33
11953791
Appl Microbiol. 1954 Mar;2(2):57-63
13149144
Antimicrob Agents Chemother. 1997 Feb;41(2):363-73
9021193
Nat Genet. 2006 Apr;38(4):489-94
16550172
Semin Respir Crit Care Med. 2006 Feb;27(1):68-81
16508883