A Historical Perspective to Decrypt AMR in Mycobacterium: From Classic Discoveries to Genomics Approaches

Antimicrobial resistance was promptly anticipated by Alexander Fleming in his Nobel lecture and, since then, it has affected virtually every drug-treated bacterial infection. This is particularly relevant for tuberculosis, the biggest infectious killer in history despite the existence of a vaccine and antibiotic treatment. The initial discovery of the first antitubercular drugs (streptomycin, para-aminosalicylic acid, isoniazid, pyrazinamide, ethambutol, and rifampicin) occurred in the mid-1900s. Since then, researchers have identified their mechanism of action, and this knowledge was otherwise used to design molecular tests to detect drug resistance polymorphisms. Later, the advent of molecular biology methods and their application to mycobacterial infections allowed the establishment of clear genotype–phenotype associations for drug resistance determinants. In recent years, the implementation of next-generation sequencing platforms has facilitated the corroboration of drug resistance determinants previously identified by classic approaches and the accumulation of knowledge on unknown mechanisms of resistance. Altogether, today researchers are equipped with a huge arsenal of molecular approaches to detect drug resistance mechanisms not only against current antimicrobials but also against drugs under development or repurposed medicines. In this chapter, we provide a historical perspective of the main events in antimicrobial resistance in the context of tuberculous and nontuberculous mycobacterial infections. We review the main genetic and genomic studies to identify drug resistance determinants, which ultimately resulted in the elaboration of the World Health Organization’s catalog of mutations and their correlation with phenotypic drug resistance in Mycobacterium.