Title:Human Tuberculosis II. M. tuberculosis Mechanisms of Genetic and Phenotypic Resistance to Anti-Tuberculosis Drugs
Volume: 23
Issue: 12
Author(s): Giampietro Sgaragli and Maria Frosini
Affiliation:
Keywords:
Genetic/phenotypic resistance, toxin/antitoxin module, DosR regulon, drug efflux pump, bacterial persistence,
metabolic adaptations.
Abstract: The great progress of knowledge of both M. tuberculosis physiology and how
human host and bacilli interact has provided fertile ground for improving diagnosis and cure
of TB infection. Once M. tuberculosis has infected humans, it elaborates strategies for evading
the risk to killing by the cells of the host immune system and by the anti-tuberculosis
(anti-TB) agents employed to cure infection. These strategies give rise to a bacterial multidrug
resistance (MDR) status. This stems firstly from genetic mutations targeting a constellation
of drug-processing mechanisms that still need full identification, as drug efflux pumps and drug activating/
inactivating enzymes (genetic resistance). Secondly, from the bacterial adaptation to stressful environmental
conditions by adopting a temporary dormancy state lasting for decades and characterized by indifference
to anti-TB drugs (phenotypic resistance or tolerance). The clarification of the strategies elaborated for
surviving by M. tuberculosis has brought to the identification in the last few years of a number of mycobacterial
molecular targets worth to exploitation for the development of novel and powerful anti-TB drugs. These
targets include drug-efflux pump systems, considered partly responsible for genetic multi-drug resistance, and
several enzymes and pump systems, as well, that sustain the metabolic adaptations of M. tuberculosis in the
host and give rise to its phenotypic drug resistance.
