New insights into TB physiology suggest untapped therapeutic opportunities

Abstract

The current regimens used to treat tuberculosis are largely comprised of serendipitously discovered drugs that are combined based on clinical experience. Despite curing millions, these drug regimens are limited by the long course of therapy, the emergence of resistance, and the persistent tissue damage that remains after treatment. The last two decades have produced only a single new drug but have represented a renaissance in our understanding of the physiology of tuberculosis infection. The advent of mycobacterial genetics, sophisticated immunological methods, and imaging technologies have transformed our understanding of bacterial physiology as well as the contribution of the host response to disease outcome. Specific alterations in bacterial metabolism, heterogeneity in bacterial state, and drug penetration all limit the effectiveness of antimicrobial therapy. This review summarizes these new biological insights and discusses strategies to exploit them for the rational development of more effective therapeutics. Three general strategies are discussed. First, our emerging insight into bacterial physiology suggests new pathways that might be targeted to accelerate therapy. Second, we explore whether the concept of genetic synergy can be used to design effective combination therapies. Finally, we outline possible approaches to modulate the host response to accentuate antibiotic efficacy. These biology-driven strategies promise to produce more effective therapies.

Keywords: antibiotics; drug discovery; host response; immunity; tuberculosis.

Fig. 1. Macrophages, B cells, and T cells surround a necrotic, caseous center in Mtb lesions

Mtb experiences a wide variety of changing stresses in the various lesion microenvironments, including altered pH (169), oxygen tension (26) and iron availability (170). In addition, the lesional penetration of standard first-line antibiotics varies greatly, exposing the bacteria to range of drug concentrations (4). Resulting changes in bacterial physiology lead to a mixed mycobacteria population in a variety of metabolic states, complicating treatment.

Fig. 2. The three types of synergy offer opportunities for novel approaches to anti-mycobacterial therapies

Classical synergy between two compounds occurs when multiple pathways are targeted simultaneously. Physiological synergy involves combination therapy with compounds that target different metabolic states. Host-pathogen synergy involves altering bacterial exposure to antibiotics by inhibiting host pathways that limit localized concentration, such as efflux pumps.