Iron acquisition strategies in mycobacteria

Fang, Zhuo; Sampson, Samantha L.; Warren, Robin M.; Pittius, Nicolaas C. Gey van; Newton-Foot, Mae

doi:10.1016/j.tube.2015.01.004

Cited by 57 publications

(55 citation statements)

References 76 publications

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“…Expression of the efflux pump is down-regulated in high iron conditions, 28 and one can expect up-regulation in low iron conditions. We checked whether the prevalence of Rv0678 RAVs was higher in isolates from female patients, but this did not appear to be the case.…”

Section: Discussionmentioning

confidence: 99%

Unexpected high prevalence of resistance-associatedRv0678variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline

Villellas

Coeck

Meehan

et al. 2016

J. Antimicrob. Chemother.

130

173

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Objectives: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. Methods: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort. Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03−0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position −11 in the intergenic region mmpS5–Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs. Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.

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Section: Discussionmentioning

confidence: 99%

Unexpected high prevalence of resistance-associatedRv0678variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline

Villellas

Coeck

Meehan

et al. 2016

J. Antimicrob. Chemother.

130

173

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“…Mycobacterium tuberculosis, like other mycobacteria, produces Fe 3ϩ -specific high-affinity low-molecular-mass (ϳ1,000 Da) compounds called siderophores for chelating the metal ion from insoluble and protein-bound iron. There are several reviews on mycobacterial siderophores and siderophore-mediated iron uptake mechanisms (5)(6)(7)(8)(9). Here, the focus is to present a comprehensive overview of iron homeostasis in M. tuberculosis and highlight its impact on the virulence of the pathogen.…”

Section: ϫ7mentioning

confidence: 99%

Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

2016

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Mycobacterium tuberculosis requires iron for normal growth but faces a limitation of the metal ion due to its low solubility at biological pH and the withholding of iron by the mammalian host. The pathogen expresses the Fe 3؉ -specific siderophores mycobactin and carboxymycobactin to chelate the metal ion from insoluble iron and the host proteins transferrin, lactoferrin, and ferritin. Siderophore-mediated iron uptake is essential for the survival of M. tuberculosis, as knockout mutants, which were defective in siderophore synthesis or uptake, failed to survive in low-iron medium and inside macrophages. But as excess iron is toxic due to its catalytic role in the generation of free radicals, regulation of iron uptake is necessary to maintain optimal levels of intracellular iron. The focus of this review is to present a comprehensive overview of iron homeostasis in M. tuberculosis that is discussed in the context of mycobactin biosynthesis, transport of iron across the mycobacterial cell envelope, and storage of excess iron. The clinical significance of the serum iron status and the expression of the iron-regulated protein HupB in tuberculosis (TB) patients is presented here, highlighting the potential of HupB as a marker, notably in extrapulmonary TB cases.

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“…Heme triggers the production of reactive oxygen species (15), which are toxic to M. tuberculosis bacilli (23), and therefore, blockade of its degradation by HO-1 may result in higher production of these metabolites and consequently enhanced bacterial killing. Another possibility is that reduced heme degradation resulting from HO-1 inhibition may lead to diminished bacterial growth by limiting the availability of nutritionally required free iron (24). …”

Section: Observationmentioning

confidence: 99%

Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

Costa

Namasivayam

Amaral

et al. 2016

mBio

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Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function.

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Iron acquisition strategies in mycobacteria

Cited by 57 publications

References 76 publications

Unexpected high prevalence of resistance-associatedRv0678variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline

Unexpected high prevalence of resistance-associatedRv0678variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline

Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes

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