Targeting persisters for tuberculosis control

Abstract

Mycobacterial persisters, the survivors from antibiotic exposure, necessitate the lengthy treatment of tuberculosis (TB) and pose a significant challenge for our control of the disease. We suggest that persisters in TB are heterogeneous in nature and comprise various proportions of the population depending on the circumstances; the mechanisms of their formation are complex and may be related to those required for persistence in chronic infection. Results from recent studies implicate multiple pathways for persister formation, including energy production, the stringent response, global regulators, the trans-translation pathway, proteasomal protein degradation, toxin-antitoxin modules, and transporter or efflux mechanisms. A combination of specifically persister-targeted approaches, such as catching them when active and susceptible either by stimulating them to "wake up" or by intermittent drug dosing, the development of new drugs, the use of appropriate drug combinations, and combined chemotherapy and immunotherapy, may be needed for more effective elimination of persisters and better treatment of TB. Variations in levels of persister formation and in host genetics can play a role in the outcome of clinical treatment, and thus, these may entail personalized treatment regimens.

Fig 1

Yin and yang of persisters and replicating bacteria and their interconversions. The yin-yang model depicts a dynamic bacterial population consisting of growing and nongrowing subpopulations in various metabolic states in a continuum (reproduced with permission from reference 83). In the growing bacterial subpopulation (yang), there is a small proportion of nongrowing or slowly growing persisters (yin). As the bacteria enter stationary phase, more persisters form, with a small number of growing bacteria. The persister subpopulation is heterogeneous and consists of a continuum of various subpopulations as a result of stochastic or induced expression of persister genes. The yin-yang model is used to explain why, after a 2-month intensive-phase treatment with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB), the remaining persister tubercle bacilli can revert to growing form which can still be killed by INH and RIF in the subsequent 4-month continuation phase of treatment. This model also explains why INH can be used for prophylactic treatment of latent TB infection, where tubercle bacilli revert from nongrowing form to growing form and become susceptible to INH. Furthermore, the yin-yang model can be used to indicate how phenotypic resistance (yin) in persisters can revert to genetic resistance (yang) in growing bacteria and vice versa.

Fig 2

Yin and yang of latent infection and overt disease and their interconversions. During overt or active disease (yang), there are both growing bacteria (majority) and nongrowing bacteria or persisters (minority). Due to host response to bacteria, there are various degrees of inflammation and disease severity, and also, bacterial populations are in a continuum. We suggest here that, as antibiotic treatment and the immune system inhibit or kill the growing bacteria, persisters remain and the infection becomes latent (yin). Latent TB infection (LTBI) (yin) due to antibiotic pressure or host immunity can have mostly nongrowing persisters and a relatively small number of growing bacteria. Among the heterogeneous persister populations there are a few “stem” persisters, which have the capacity to initiate disease or cause reactivation.