Reply to Jones and Niederweis

Reddy, P. Vineel; Puri, Rupangi Verma; Chauhan, Priyanka; Kar, Ritika; Rohilla, Akshay; Khera, Aparna; Tyagi, Anil K.

doi:10.1093/infdis/jit605

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…However, when Mtb resides in an environment where the heme-iron supply is not limited, MhuD's ability to accommodate two hemes per monomer could provide an avenue for heme storage analogous the iron-storage ferritin proteins, Mtb BfrA and BfrB. 201 Furthermore, MhuD-diheme inactivation may also provide a regulatory mechanism to prevent heme degradation under iron rich conditions.…”

Section: 42mentioning

confidence: 99%

Iron Acquisition in Mycobacterium tuberculosis

Chao¹,

Sieminski²,

Owens

et al. 2018

Chem. Rev.

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The highly contagious disease tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an alarming rate. Like all human pathogens, Mtb requires iron for growth and virulence. Consequently, Mtb iron transport is an emerging drug target. However, the development of anti-TB drugs aimed at these metabolic pathways have been restricted by the dearth of information on Mtb iron acquisition. In this review, we describe the multiple strategies utilized by Mtb to acquire ferric iron and heme-iron. Mtb iron uptake is a complex process, requiring biosynthesis and subsequent export of Mtb siderophores, followed by ferric iron scavenging and ferric-siderophore import into Mtb. Additionally, Mtb possesses two possible heme uptake pathways, and an Mtb-specific mechanism of heme degradation that yields iron and novel heme-degradation products. We conclude with perspectives for potential therapeutics that could directly target Mtb heme and iron uptake machineries. We also highlight how hijacking Mtb heme and iron acquisition pathways for drug import may facilitate drug transport through the notoriously impregnable Mtb cell-wall.

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Section: 42mentioning

confidence: 99%

Iron Acquisition in Mycobacterium tuberculosis

Chao¹,

Sieminski²,

Owens

et al. 2018

Chem. Rev.

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“…The relative contribution of each mechanism for iron mobilization in vivo is unknown, and both may play a role during different stages of infection. Mtb mutants unable to produce mycobactins cannot replicate under iron-restricted conditions and are cleared in vivo , thereby confirming the importance of mycobactin-mediated iron acquisition in Mtb …”

Section: Introductionmentioning

confidence: 82%

“…Mtb mutants unable to produce mycobactins cannot replicate under iron-restricted conditions and are cleared in vivo , thereby confirming the importance of mycobactin-mediated iron acquisition in Mtb . 8 …”

Section: Introductionmentioning

confidence: 99%

Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis

Liu

Aldrich

2015

J. Org. Chem.

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Mycobactins are small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (Mtb) for iron mobilization. The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate into salicylic acid via isochorismate. We report the design, synthesis and biochemical evaluation of an inhibitor based on the putative transition-state (TS) for the isochorismatase partial reaction of MbtI. The inhibitor mimics the hypothesized charge build-up at C-4 of chorismate in the TS as well as C-O bond-formation at C-6. Another important design element of the inhibitor is replacement of the labile pyruvate side-chain in chorismate with a stable C-linked propionate isostere. We developed a stereocontrolled synthesis of the highly functionalized cyclohexene inhibitor that features an asymmetric aldol reaction using a titanium enolate, diastereoselective Grignard addition to a tert-butanesulfinyl aldimine, and ring closing olefin metathesis as key steps.

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