Targeting the Mycobacterium tuberculosis Stringent Response as a Strategy for Shortening Tuberculosis Treatment

Danchik, Carina; Wang, Siqing; Karakousis, Petros C.

doi:10.3389/fmicb.2021.744167

Cited by 12 publications

(11 citation statements)

References 62 publications

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“…ppGpp (guanosine tetraphosphate) is an alarmone produced by bacteria which regulates the stringent response and is synthesized by the protein Rel in Mtb ( Avarbock et al., 1999 ). Multiple studies have shed light on the role played by ppGpp in diverse mycobacterial species ( Chakrabarty, 1998 ; Ojha et al., 2000 ; Primm et al., 2000 ; Manganelli, 2007 ; Wu et al., 2016a ; Prusa et al., 2018 ; Bhaskar et al., 2018 ; Danchik et al., 2021 ; Hunt-Serracin et al., 2022 ). In other organisms, the stringent response is known to play an important role in the formation of the VBNC population.…”

Section: Mechanisms Underlying Heterogeneity In Culturabilitymentioning

confidence: 99%

Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: A review

Mishra

Saito²

2022

Front. Cell. Infect. Microbiol.

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The clinical manifestations of tuberculosis (TB) vary widely in severity, site of infection, and outcomes of treatment—leading to simultaneous efforts to individualize therapy safely and to search for shorter regimens that can be successfully used across the clinical spectrum. In these endeavors, clinicians and researchers alike employ mycobacterial culture in rich media. However, even within the same patient, individual bacilli among the population can exhibit substantial variability in their culturability. Bacilli in vitro also demonstrate substantial heterogeneity in replication rate and cultivation requirements, as well as susceptibility to killing by antimicrobials. Understanding parallels in clinical, ex vivo and in vitro growth phenotype diversity may be key to identifying those phenotypes responsible for treatment failure, relapse, and the reactivation of bacilli that progresses TB infection to disease. This review briefly summarizes the current role of mycobacterial culture in the care of patients with TB and the ex vivo evidence of variability in TB culturability. We then discuss current advances in in vitro models that study heterogenous subpopulations within a genetically identical bulk culture, with an emphasis on the effect of oxidative stress on bacillary cultivation requirements. The review highlights the complexity that heterogeneity in mycobacterial growth brings to the interpretation of culture in clinical settings and research. It also underscores the intricacies present in the interplay between growth phenotypes and antimicrobial susceptibility. Better understanding of population dynamics and growth requirements over time and space promises to aid both the attempts to individualize TB treatment and to find uniformly effective therapies.

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Section: Mechanisms Underlying Heterogeneity In Culturabilitymentioning

confidence: 99%

Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: A review

Mishra

Saito²

2022

Front. Cell. Infect. Microbiol.

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“…One of the fundamental problems in research aimed at improving public health is reducing the incidence rate, ineffective treatment and mortality linked to recurrent bacterial infections [1], of which tuberculosis occupies the leading place in terms of these indicators [2,3]. This is largely due to the specific properties of the causative agent of tuberculosis Mycobacterium tuberculosis, which has a pronounced ability for persistence [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, to resolve the problem of bacterial persistence, novel and more effective treatment strategies are required. One of the possible ways to solve it may be the development of new compounds that compromise bacterial adaptations to stress, such as the stringent response [1,9], the synthesis of (p)ppGpp alarmones signaling molecules, which act as positive regulators of bacterial persistence [10].…”

Section: Introductionmentioning

confidence: 99%

DMNP, a Synthetic Analog of Erogorgiaene, Inhibits the ppGpp Synthetase Activity of the Small Alarmone Synthetase RelZ

Sidorov

Ткаченко²

2023

BIO Web Conf.

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Suppression of the stringent response is a promising strategy for the treatment of persistent bacterial infections. A novel class of compounds having a mechanism of action based on alarmone synthetase inhibition and suppressing the synthesis of (p)ppGpp alarmones in bacteria may provide a more effective treatment for latent infections and resolve problems associated with bacterial persistence. Conventional antibiotics primarily act on actively growing bacteria, but they are inactive against persister cells with a slowed metabolism. Alarmone synthetase inhibitors have antipersister properties that may enhance conventional antibiotics’ antibacterial action. Two groups of RSH proteins are responsible for the synthesis of alarmones: long RelA/SpoT homologs and small alarmone synthetases. Many species of bacteria possess both types of enzymes. Despite the fact that a number of inhibitors of bifunctional long synthetases/hydrolases have been described to date, their properties with respect to monofunctional small alarmone synthetases have been studied poorly. This study investigated the effect of the alarmone synthetase inhibitor DMNP on the purified RelZ small alarmone synthetase protein from Mycolicibacterium smegmatis.

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“…One of the key bacterial pathways implicated in antibiotic tolerance is the stringent response, which is regulated by the (p)ppGpp synthase/hydrolase, Rel Mtb (12, 13). Rel Mtb deficiency results in defective Mtb survival under nutrient starvation (14), in mouse lungs (15) and mouse hypoxic granulomas (16), reduced virulence in guinea pigs (17) and C3HeB/FeJ mice (18), and increased susceptibility of Mtb to INH in mouse lungs (18), rendering Rel Mtb an attractive target for novel anitubercular therapies, including for drug-resistant TB (13).…”

Section: Introductionmentioning

confidence: 99%

“…The need for prolonged TB treatment is believed to reflect the unique ability of a subpopulation of Mycobacterium tuberculosis (Mtb) bacilli within the infected host to remain in a nonreplicating, persistent state (7) characterized by tolerance to first-line anti-TB drugs, like INH, which more effectively targets actively dividing bacilli (8)(9)(10)(11). One of the key bacterial pathways implicated in antibiotic tolerance is the stringent response, which is regulated by the (p)ppGpp synthase/hydrolase, RelMtb (12,13). RelMtb deficiency results in defective Mtb survival under nutrient starvation (14), in mouse lungs (15) and mouse hypoxic granulomas (16), reduced virulence in guinea pigs (17) and C3HeB/FeJ mice (18), and increased susceptibility of Mtb to INH in mouse lungs (18), rendering RelMtb an attractive target for novel anitubercular therapies, including for drug-resistant TB (13).…”

Section: Introductionmentioning

confidence: 99%

An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis

Karanika

Gordy

Neupane

et al. 2022

Preprint

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Lengthy tuberculosis (TB) treatment is required to address the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We developed a novel therapeutic DNA vaccine construct involving fusion of the relMtb gene with the immature dendritic cell-targeting gene encoding chemokine MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that the intramuscular MIP-3α/relMtb (fusion) vaccine potentiates isoniazid activity more than a similar DNA vaccine expressing relMtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log10 colony-forming units, P=0.0001), inducing pronounced Mtb-protective immune signatures. The intranasal fusion vaccine, an approach combining relMtb fusion to MIP-3α and intranasal delivery, demonstrated the greatest therapeutic effect compared to each approach alone, as evidenced by robust Th1 and Th17 responses systemically and locally and the greatest mycobactericidal activity when combined with isoniazid (absolute reduction of Mtb burden: 1.13 log10, P<0.0001, when compared to the intramuscular vaccine targeting relMtb alone). This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serve as proof-of-concept for treating other chronic infections.

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Targeting the Mycobacterium tuberculosis Stringent Response as a Strategy for Shortening Tuberculosis Treatment

Cited by 12 publications

References 62 publications

Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: A review

Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: A review

DMNP, a Synthetic Analog of Erogorgiaene, Inhibits the ppGpp Synthetase Activity of the Small Alarmone Synthetase RelZ

An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis

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