Table 4. Experimentally determined epistatic interactions between single mutations in the extended-spectrum antibiotic resistance community network.

M1	M1 Growth [cm]	M2	M2 Growth [cm]	M1_M2 Growth [cm]	M1_M2 - (M1+M2) [cm]	Significant Epistastic Effect*
Q39R	2.09	G238S	9.61	7.76	-2.35
Q39R	2.09	E240K	1.58	2.16	0.08
L40W	2.08	R164H	3.43	2.13	-1.79	negative
L51P	1.93	E104K	2.20	1.65	-0.89	negative
L51P	1.93	R164H	3.43	1.90	-1.87	negative
E104K	2.20	H153R	2.17	2.73	-0.05
E104K	2.20	R164H	3.43	8.42	4.38	positive
E104K	2.20	I173V	2.10	10.84	8.13	positive
E104K	2.20	M182T	2.15	2.82	0.06
E104K	2.20	K215E	1.90	2.39	-0.12
E104K	2.20	A224V	1.86	1.90	-0.57
E104K	2.20	G238S	9.61	16.83	6.61	positive
R120S	1.94	G238S	9.61	7.22	-2.74	negative
H153R	2.17	G238S	9.61	11.50	1.31
R164H	3.43	I173V	2.10	6.95	3.01	positive
R164H	3.43	A224V	1.86	3.90	0.20
R164H	3.43	E240K	1.58	9.48	6.06	positive
I173V	2.10	E240K	1.58	3.62	1.53	positive
M182T	2.15	G238S	9.61	16.17	6.00	positive
K215E	1.90	G238S	9.61	6.34	-3.58	negative
G238S	9.61	E240K	1.58	12.04	2.44
G238S	9.61	T265M	N/A	10.84	N/A

Mutated residues (columns 1 and 3) and their individual cefotaxime resistance levels (columns 2 and 4) are compared to resistance levels when they occur together in the same sequence (column 5). The level of cefotaxime resistance (an indicator of extended-spectrum antibiotic resistance) is shown in centimeters of linear growth on a 0.04 µg/ml cefotaxime gradient. The difference between the combined effect (column 5) and the sum of the individual effects (column 2 + column 4), which represents epistasis, is shown in column 6.

*Significant epistatic effect  =  differences that exceed the margin of standard error (for the number of replicates (n), refer to Table S4). The sign of significant sign-epistatic interactions is shown in column 7. These interactions are mapped onto edges in our extended-spectrum community network (Figure 4A,B). Six interactions that were previously reported as positive are highlighted here in bold.