Tolerance and Persistence to Drugs: A Main Challenge in the Fight Against Mycobacterium tuberculosis

Abstract

The treatment of tuberculosis is extremely long. One of the reasons why Mycobacterium tuberculosis elimination from the organism takes so long is that in particular environmental conditions it can become tolerant to drugs and/or develop persisters able to survive killing even from very high drug concentrations. Tolerance develops in response to a harsh environment exposure encountered by bacteria during infection, mainly due to the action of the immune system, whereas persistence results from the presence of heterogeneous bacterial populations with different degrees of drug sensitivity, and can be induced by exposure to stress conditions. Here, we review the actual knowledge on the stress response mechanisms enacted by M. tuberculosis during infection, which leads to increased drug tolerance or development of a highly drug-resistant subpopulation.

Keywords: mycobacteria; persistence; stringent response; tolerance; tuberculosis.

Figure 1

Theoretical drug killing curves of different bacterial populations: sensitive (red), persistant (blue), and tolerant (green). When a persistant subpopulation is present in a bacterial culture, the shape of the killing curve appears as bimodal. Explanation in the text.

Figure 2

Bipolar growth of mycobacteria. Rapid cell elongation occurs at the older pole (here arbitrarily shown on the left) that grows faster than the newly formed pole. This asymmetric division generates a heterogeneous population in both size and elongation rate. Different individuals of the heterogeneous population can have different drugs sensitivity.

Figure 3

Some bacteria can survive rifampicin treatment due to the presence in their cytoplasm of high concentration of rifampicin-resistant RNA polymerase (dark blue) due to rpoB mistranslation. These cells will have the opportunity to overexpress the wild type RNA polymerase (red) from its secondary promoter and gain transient resistance to the drug.

Figure 4

Schematic representation of the effects of (p)ppGpp accumulation in Mycobacterium tuberculosis: the inhibition of the exopolyphosphatases PPX1 and PPX2 leads to poly P accumulation and to the activation of the mprAB-sigE-rel_mtb signaling pathway. Poly P accumulation is enhanced by the induction of ppk1.