Relation of Mycobacterium tuberculosis mutations at katG315 and inhA-15 with drug resistance profile, genetic background, and clustering in Argentina

•In Argentina, tuberculosis resistance profile and spread are genotype-dependent.•Isoniazid-resistance conferring mutations katG315 and inhA-15 rarely concur.•Certain genotypes preferentially harbor one, the other, or none of both mutations.•katG315 mutation associates to resistance to other drugs and disease transmission.•Isoniazid-resistant strains wild-type for both gene sites are rarely transmitted.

We analyzed 362 isoniazid-resistant clinical isolates of Mycobacterium tuberculosis obtained countrywide for the presence of mutation at katG315 and inhA-15 in relation to genotype, pattern of phenotypic resistance to other drugs, and ability to spread. We found the following mutation frequencies: katG315MUT/inhA-15wt 53.0%, katG315wt/inhA-15MUT 27.4%, katG315wt/inhA-15wt 19.3%, and katG315MUT/inhA-15MUT only 0.3%. Mutation at katG315 associated with the LAM superfamily; mutation at inhA-15 associated with the S family and the T1 Tuscany genotype; the combination katG315wt/inhA-15wt associated with the T1 Ghana genotype. Isolates harboring katG315MUT/inhA-15wt tended to accumulate resistance to other drugs and were more frequently found in cluster; isolates harboring katG315wt/inhA-15wt were more frequently found as orphan isolates. Although epidemiological and host factors could also be modulating the events observed, in Argentina, the systematic genotyping of drug resistant clinical isolates could help to predict an enhanced risk of transmission and a propensity to develop resistance to increasing numbers of drugs.