RESUMEN
INTRODUCTION: Microorganisms of clinical importance frequently develop resistance to drug therapy, now a growing problem. The experience with Mycobacterium tuberculosis is a representative example of increasing multi-drug resistance. To avoid reaching a crisis in which patients could be left without adequate treatment, a new strategy is needed. Anti-microbial therapy has historically targeted the mechanisms rather than origin of drug resistance, thus allowing microorganisms to adapt and survive. AREAS COVERED: This contribution analyses the historical development (1943-2020) of the evolution of multi-drug resistance by M. tuberculosis strains in light of Darwin's and Lamarck's theories of evolution. EXPERT OPINION: Regarding the molecular origin of microbial drug resistance, genetic mutations and epigenetic modifications are known to participate. The analysis of the history of drug resistance by M. tuberculosis evidences a gradual development of resistance to some antibiotics, undoubtedly due to random mutations together with natural selection based on environmental pressures (e.g., antibiotics), representing Darwin's idea. More rapid adaptation of M. tuberculosis to new antibiotic treatments has also occurred, probably because of heritable acquired characteristics, evidencing Lamarck's proposal. Therefore, microbial infections should be treated with an antibiotic producing null or low mutagenic activity along with a resistance inhibitor, preferably in a single medication.