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Background  Drug resistance displays a problem for the therapy of  Mycobacterium tuberculosis  infections. For molecular resistance testing, it is essential to have precise knowledge on genomic variations involved in resistance development. However, data from high-incidence settings are only sparely available. Therefore we performed a systematic approach and analyzed a total of 97  M. tuberculosis  strains from previously treated patients in Sierra Leone for mutations in  kat G,  rpo B,  rrs ,  rps L,  gid B,  emb B,  pnc A and where applicable in  inh A and  ahp C. Of the strains investigated 50 were either mono- or poly-resistant to isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide or MDR and 47 fully susceptible strains served as controls.    Results  The majority of isoniazid and rifampin resistant strains had mutations in  kat G315 (71.9%) and  rpo B531 (50%). However,  rpo B mutations in codons 511, 516 and 533 were also detected in five rifampin susceptible strains. MIC determinations revealed low-level rifampin resistance for those strains. Thus, the sensitivity and specificity of sequencing of  kat G for detection of drug resistance were 86.7% and 100% and for sequencing of  rpo B 100% and 93.8%, respectively.  Strikingly, none of the streptomycin resistant strains had mutations in  rrs , but 47.5% harboured mutations in  rps L. Further changes were detected in  gid B. Among ethambutol resistant strains 46.7% had mutations at  emb B306. Pyrazinamide resistant strains displayed a variety of mutations throughout  pnc A. The specificities of sequencing of  rps L,  emb B and  pnc A for resistance detection were high (96-100%), whereas sensitivities were lower (48.8%, 73.3%, 70%).    Conclusions  Our study reveals a good correlation between data from molecular and phenotypic resistance testing in this high-incidence setting. However, the fact that particular mutations in  rpo B are not linked to high-level resistance is challenging and demonstrates that careful interpretation of molecular resistance assays is mandatory. In addition, certain variations, especially in  gid B, appear to be phylogenetically informative polymorphisms rather than markers for drug resistance.

Sequence analysis for detection of first-line drug resistance in Mycobacterium tuberculosis strains from a high-incidence setting