List of confidence-graded mutations associated with phenotypic drug resistance as determined by best confidence values
Drug (phenotypic testing) | Gene | High-confidence mutations | Moderate-confidence mutations | Minimal-confidence mutations | No association with resistance |
First-line | |||||
Rifampicin (R) | rpoB | F505V+D516Y, S512T, Q513H+L533P, Q513-F514ins, Q513K, Q513L, Q513P, F514dupl, M515I+D516Y, D516A, D516F, D516G, D516G+L533P, D516ins, D516N, D516V, Del N518, S522Q, H526C, H526D, H526F, H526G, H526L, H526R, H526Y S531F, S531L, S531Q, S531W, S531Y, D626E | D516Y, S522L, H526P, L533P | L511P, H526N, I572F | |
Isoniazid (H) | inhA-mabA | g-102a#,¶ | c-15t | g-102a#,¶, t-80g, g-47c, T4I | |
katG | S315I, S315N, S315T, pooled frameshifts and premature stop codons | A110V, R463L, L499M | |||
furA | L68F | ||||
mshA | A187V#,¶ | N111S | |||
Second-line (group A) | |||||
Moxifloxacin (MFX) | gyrA | G88C, A90V, S91P, D94A, D94G, D94N, D94Y | E21Q, S95T, G247S, G668D, V712L | ||
Ofloxacin (OFX)/levofloxacin (LFX) | gyrA | G88A, G88C, S91P, A90V, D94A, D94G, D94H, D94N, D94Y | D89N | E21Q, T80A, S95T, G247S, G668D, V712L | |
gyrB | E459K, A504V | ||||
Second-line (group B) | |||||
Amikacin (AM) | rrs | a1401g, g1484t | |||
Kanamycin (KM) | eis | c-14t, g-10a | g-37t, c-12t | a1338c | |
rrs | a514c#, a1401g, c1402t, g1484t | ||||
rrs+eis | rrs c517t# + eis g-37t | ||||
Capreomycin (CM) | rrs | a1401g, c1402t, g1484t | c517t | ||
tlyA | N236K, pooled frameshifts and premature stop codons | D149H | |||
Streptomycin (S) | rpsL | K43R, K43T, K88Q, K88R, T40I | |||
rrs | a1401g#, a514c, a514t, c462t, c513t, c517t | ||||
gidB | E92D#,¶ | L16R, V110G, pooled frameshifts and premature stop codons | |||
Second-line (group C) | |||||
Ethionamide and prothionamide (ETO/PTO) | inhA | c-15t+I194T, c-15t+S49A | c-15t | ||
ethA | Q347Stop | ||||
Second-line (group D) | |||||
Pyrazinamide (Z) | pncA | t-12c, a-11g, t-7c, A3E, L4S, I6T, V7G, D8E, D8G, D8N, Q10P, D12A, D12N, C14R, G17D, L19P, G24D, Y34D, A46V, K48T, D49G, D49N, H51Q, H51R, P54S, H57D¶, H57P, H57R, H57Y, S59P, P62L, P62Q, D63G, S66P, S67P, W68C, W68R, H71D, H71Q, H71Y, C72R, T76P, H82R, L85P, L85R, F94L, F94S, K96N, K96R, G97C, G97D, G97S, Y103H, S104R, G108R, L116P, L116R, L120P, R123P, V125F, V125G, V128G, G132A, G132D, G132S, A134V, T135N, T135P, H137P, C138Y, V139G, V139L, Q141P, T142A, T142K, T142M, indel - R148ins (inframe), L151S, V155G, L159P, T160P, G162D, T168P, L172P, M175T, M175V, V180F, V180G, Pooled frameshifts and premature stop codons | V7G, Q10R, P54L, W68G, K96E, K96T, A171E, M175I | D12G, F58L, H71R, I133T, V139A | indel - c-125del, I31T, L35R, T47A, I6L, K48T, T114M |
The table includes all the mutations graded according to the proposed standardised approach for providing confidence levels to their association with phenotypic drug resistance. Standard type represents associations based on nominal p-values (putative); bold type represents associations based on corrected p-values. The rationale for pooling insertions/deletions and nonsense mutations can be found in online supplementary material 5. Tables 1 and 2 provide the details of the data included in the grading system and the definitions for the confidence categories. Indeterminate mutations were not included in the table and can be found in online supplementary material 8. Drugs were classified based on the updated guidelines for short and individualised regimens [4]. #: six associations were not considered for further analysis as there was probably no causative relationship between these genetic changes and the resistance to the antibiotic in question; ¶: genotype-specific mutation.