Antimicrobial efflux pumps and Mycobacterium tuberculosis drug tolerance: evolutionary considerations

Abstract

The need for lengthy treatment to cure tuberculosis stems from phenotypic drug resistance, also known as drug tolerance, which has been previously attributed to slowed bacterial growth in vivo. We discuss recent findings that challenge this model and instead implicate macrophage-induced mycobacterial efflux pumps in antimicrobial tolerance. Although mycobacterial efflux pumps may have originally served to protect against environmental toxins, in the pathogenic mycobacteria, they appear to have been repurposed for intracellular growth. In this light, we discuss the potential of efflux pump inhibitors such as verapamil to shorten tuberculosis treatment by their dual inhibition of tolerance and growth.

Figure 1. Model for Efflux Pump Inhibitor Action in Mycobacterium tuberculosis (Mtb)

Efflux pump expression is induced in Mtb following macrophage residence, perhaps stimulated by macrophage antimicrobial peptides. With antimicrobial treatment alone, non-tolerant bacteria are killed, but tolerant bacteria survive and multiply within the macrophage. When antimicrobials are given in conjunction with an efflux pump inhibitor, the tolerant bacteria are killed along with non-tolerant bacteria. Note that in this simplified diagram there is no attempt to differentiate between mycobacterial residence in the cytoplasm versus the phagosome. Modified from (Adams et al. 2011)