A competitive trade-off limits the selective advantage of increased antibiotic production.
In structured environments, antibiotic-producing microorganisms can gain a selective advantage by inhibiting nearby competing species1. However, despite their genetic potential2,3, natural isolates often make only small amounts of antibiotics, and laboratory evolution can lead to loss rather than enhancement of antibiotic production4. Here, we show that, due to competition with antibiotic-resistant cheater cells, increased levels of antibiotic production can actually decrease the selective advantage to producers. Competing fluorescently labelled Escherichia coli colicin producers with non-producing resistant and sensitive strains on solid media, we found that although producer colonies can greatly benefit from the inhibition of nearby sensitive colonies, this benefit is shared with resistant colonies growing in their vicinity. A simple model, which accounts for such local competitive and inhibitory interactions, suggests that the advantage of producers varies non-monotonically with the amount of production. Indeed, experimentally varying the amount of production shows a peak in selection for producers, reflecting a trade-off between benefit gained by inhibiting sensitive competitors and loss due to an increased contribution to resistant cheater colonies. These results help explain the low level of antibiotic production observed for natural species and can help direct laboratory evolution experiments selecting for increased or novel production of antibiotics.
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Ylaine
Y
Gerardin
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Michael
M
Springer
Faculty of Biology and Faculty of Computer Science, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
Roy
R
Kishony
Proc Natl Acad Sci U S A. 1976 Nov;73(11):3989-93
1069283
Nature. 2002 May 9;417(6885):141-7
12000953
Nature. 2002 Jul 11;418(6894):171-4
12110887
Appl Environ Microbiol. 2002 Oct;68(10):4731-9
12324314
Biochimie. 2002 May-Jun;84(5-6):357-64
12423779
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17025-30
12482953
Nature. 2004 Mar 25;428(6981):412-4
15042087
Metab Eng. 2004 Oct;6(4):300-12
15491860
Science. 2006 Jan 20;311(5759):374-7
16424339
Nat Rev Microbiol. 2006 Apr;4(4):249-58
16501584
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19484-9
17148599
Genetics. 1979 Apr;91(4):627-37
17248902
Nat Biotechnol. 2007 Apr;25(4):447-53
17369815
Nature. 2007 Nov 15;450(7168):411-4
18004383
Metab Eng. 2008 Sep;10(5):281-92
18674632
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):280-5
19114652
Nature. 2009 May 14;459(7244):253-6
19349960
Curr Biol. 2009 Jun 9;19(11):R437-41
19515346
Evolution. 2010 Feb 1;64(2):522-33
19674096
J Bacteriol. 2010 Jan;192(1):365-9
19880596
Nat Rev Microbiol. 2010 Jan;8(1):15-25
19946288
Mol Syst Biol. 2010 Sep 7;6:407
20823845
PLoS One. 2010 Dec 08;5(12):e15179
21209699
Nat Chem Biol. 2011 Dec 15;8(1):2-5
22173342
PLoS One. 2012;7(3):e33727
22470465
Mol Syst Biol. 2013 Aug 06;9:683
23917989
Nat Rev Microbiol. 2014 Feb;12(2):137-48
24384601
J R Soc Interface. 2014 May 07;11(96):20140172
24806706
Nat Rev Microbiol. 2014 Jul;12(7):465-78
24861036
Nature. 2015 May 28;521(7553):516-9
25992546
Nat Commun. 2016 Jan 20;7:10333
26787239
Evolution. 1998 Oct;52(5):1270-1276
28565393
Mol Gen Genet. 1985;198(3):465-72
3892228
J Mol Biol. 1980 May 15;139(2):147-61
6447794
Proc Natl Acad Sci U S A. 1981 Oct;78(10):6324-8
7031647
Nucleic Acids Res. 1997 Mar 15;25(6):1203-10
9092630