Inhibiting DosRST As a New Approach to Tuberculosis Therapy

Abstract

Progress against tuberculosis (TB) requires faster-acting drugs. Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious disease and its treatment is challenging and lengthy. Mtb is remarkably successful, in part, due to its ability to become dormant in response to host immune pressures. The DosRST two-component regulatory system is induced by hypoxia, nitric oxide and carbon monoxide and remodels Mtb physiology to promote nonreplicating persistence (NRP). NRP bacteria are thought to play a role in the long course of TB treatment. Therefore, inhibitors of DosRST-dependent adaptation may function to kill this reservoir of persisters and potentially shorten therapy. This review examines the function of DosRST, newly discovered compounds that inhibit DosRST signaling and considers future development of DosRST inhibitors as adjunct therapies.

The ctpF Gene Encoding a Calcium P-Type ATPase of the Plasma Membrane Contributes to Full Virulence of Mycobacterium tuberculosis

“…Furthermore, it has been established that the DosR regulon is required for Mtb to establish an NRP state and survive during hypoxia [ 42 ], which supports the idea that CtpF is an interesting attenuation target to design novel vaccines, and may even be a new target for anti-TB compounds [ 38 , 70 ].…”

“…As stated above, the expression of ctpF is controlled by DosR [ 44 ], which is involved in maintaining low bacterial growth under unfavorable conditions (such as in granulomas), entering into a dormant state and maintaining it for a long time within the host [ 41 , 42 , 43 , 44 , 45 , 56 ]. Therefore, we used qRT-PCR to compare the absolute transcription levels of ctpF in a model of progressive pulmonary TB and latent TB infection in BALB/c mice ( Figure 6 ).…”

“…It had been previously established that CtpF is a membrane transporter involved in calcium pumping outside mycobacterial cells, and in the response to oxidative/nitrosative stress [ 40 ]. Moreover, ctpF is the only Mtb P-type ATPase gene regulated by the global latency regulator (DosR), which is involved in the adaptation of bacilli to anaerobic environments, acidic pH, starvation and high nitric oxide (NO) intermediates inside macrophages and granulomas; thus, ctpF promotes a non-replicating persistence (NRP) or dormancy state [ 41 , 42 , 43 , 44 , 45 ]. Therefore, the fact that ctpF is part of the DosR regulon and its expression is activated in response to redox stress (a condition faced by the tubercle bacillus in the phagosomal environment) suggests that the role of this transporter is critical during Mtb infection.…”

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

“…Oxygen levels in cells are detected through more or less complex biochemical sensors, depending on the organism [ 156 ]. In the case of M.tb , its presence or absence is determined by DevS and DosT, two oxygen heme-based sensors, which function like a two-component system along with DevR, a response regulator [ 157 ]. By sensing variations in the levels of oxygen in the surrounding media, these promote a series of metabolic changes in the bacillus, initiating the process of latency.…”

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

“…This latter TCS (given different names in different species (YycFG, WalRK, VicRK)), has attracted particular attention with regard to novel chemicals agents that inhibit its activities, and although the essentiality of such TCSs often resides with the RR component, many inhibitor studies have focused on the membrane-located SHK components (see [ 61 ] for a recent listing of some examples). Several additional recent reviews of inhibitors of SHK and/or RR components have been published [ 17 , 18 , 21 , 23 , 25 , 62 , 63 , 64 , 65 , 66 ].…”