Association of gyrA/B mutations and resistance levels to fluoroquinolones in clinical isolates of Mycobacterium tuberculosis

Figures & data

Table 1 The mutation profiles and the fluoroquinolone MICs of the 80 ofloxacin-resistant M. tuberculosis isolates

Substitution					MIC (mg/L)			MIC50 (mg/L)
gyrA	gyrB	n	OFX	MOX	GAT	Total number with this mutation (%)	OFX	MOX	GAT
G88A (GGC→GCC)	WT^a	1	8.0	1.0	1.0	1 (1.25%)	8.0	1.0	1.0
D89G (GAG→AAG)	WT	1	8.0	2.0	0.5	1 (1.25%)	8.0	2.0	0.5
A90V (GCG→GTG)	WT	1	2.0	1.0	0.25	18 (22.50%)	4.0	1.0	0.5
		1	2.0	1.0	0.5
		1	2.0	1.0	1.0
		1	4.0	0.5	0.5
		1	4.0	1.0	0.25
		8	4.0	1.0	0.5
		1	4.0	1.0	1.0
		1	4.0	2.0	1.0
		1	8.0	1.0	1.0
		1	8.0	2.0	1.0
		1	16.0	4.0	2.0
A90V (GCG→GTG)	E498Q (GAA→CAA)	1	4.0	0.5	0.5	1 (1.25%)	4.0	0.5	0.5
A90V (GCG→GTG)	G551R (GGG→AGG)	1	2.0	0.5	0.5	2 (2.50%)	3.0	0.75	0.5
		1	4.0	1.0	0.5
A90V (GCG→GTG)	N538S (AAC→AGC)	1	2.0	0.5	0.5	1 (1.25%)	2.0	0.5	0.5
S91P (TCG→CCG)	WT	1	2.0	1.0	0.5	1 (1.25%)	2.0	1.0	0.5
D94A (GAC→GCC)	WT	3	2.0	0.5	0.5	13 (16.25%)	4.0	1.0	0.5
		1	2.0	0.5	0.25
		1	2.0	1.0	0.5
		1	2.0	1.0	1.0
		4	4.0	1.0	0.5
		1	4.0	1.0	1.0
		1	8.0	1.0	0.5
		1	8.0	2.0	1.0
D94G (GAC→GGC)	WT	1	4.0	0.5	0.5	18 (22.50%)	8.0	2.0	1.0
		1	4.0	1.0	0.5
		2	4.0	1.0	1.0
		1	4.0	4.0	1.0
		4	8.0	2.0	0.5
		4	8.0	2.0	1.0
		3	8.0	2.0	2.0
		1	16.0	4.0	2.0
		1	16.0	4.0	4.0
D94G (GAC→GGC)	E498Q (GAA→CAA)	1	8.0	2.0	1.0	1 (1.25%)	8.0	2.0	1.0
D94N (GAC→AAC)	WT	1	2.0	0.5	0.5	12 (15.00%)	8.0	2.0	1.0
		1	4.0	2.0	1.0
		3	8.0	2.0	1.0
		2	8.0	2.0	2.0
		2	8.0	4.0	1.0
		1	16.0	4.0	2.0
		1	16.0	8.0	1.0
		1	32.0	4.0	1.0
D94N (GAC→AAC)	G551R (GGG→AGG)	1	8.0	2.0	2.0	1 (1.25%)	8.0	2.0	2.0
D94Y (GAC→TAC)	WT	1	4.0	1.0	0.5	4 (5.00%)	8.0	2.0	0.5
		1	8.0	2.0	0.5
		2	8.0	2.0	1.0
WT	E498Q (GAA→CAA)	1	4.0	1.0	0.5	1 (1.25%)	4.0	1.0	0.5
WT	A543V (GCG→GTG)	1	2.0	0.5	0.25	1 (1.25%)	2.0	0.5	0.25
WT	G551R (GGG→AGG)	1	8.0	2.0	1.0	1 (1.25%)	8.0	2.0	1.0
WT	WT	1	2.0	0.5	<0.125	3 (3.75%)	2.0	2.0	0.5
		1	2.0	2.0	0.5
		1	4.0	0.5	0.25
Total						80 (100%)	4.0	1.0	0.5
H37Rv		1	<0.5	<0.125	<0.125	1	<0.5	<0.125	<0.125

Abbreviations: GAT, gatifloxacin; MOX, moxifloxacin; OFX, ofloxacin.

a Wild type.

Figure 1 MICs of the three fluoroquinolones for isolates carrying the four most frequent mutations. The transverse lines represent the median MIC for each drug. The D94G and D94N mutations were significantly associated with higher resistance to all three drugs than the A90V and D94A mutations (pair-wise Mann–Whitney U test, Table 2).

Table 2 Pair-wise comparison of resistance levels of isolates carrying A90V/D94A/D94G/D94N mutations, using the Mann–Whitney U test.

	Ofloxacin		Moxifloxacin		Gatifloxacin
Grouping mutations	Mann–Whitney U	P value^a	Mann–Whitney U	P value^a	Mann–Whitney U	P value^a
A90V/D94A	86.000	0.168	82.000	0.079	107.500	0.661
A90V/D94G	68.000	0.001	71.000	0.002	92.500	0.019
A90V/D94N	40.500	0.002	31.500	0.001	40.500	0.002
D94A/D94G	33.500	<0.001	31.500	<0.001	55.500	0.008
D94A/D94N	21.500	0.001	14.000	<0.001	19.500	0.001
D94G/D94N	88.000	0.415	74.500	0.158	92.000	0.518

a P value in bold: significant below the level of 0.05.