Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis

Juárez-Hernández, Raúl E.; Zhu, Helen He; Miller, Marvin J.

doi:10.1007/978-3-319-00303-0_5

Cited by 2 publications

(3 citation statements)

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“…Additional extensive SAR of differentially modified mycobactins has been summarized elsewhere. 63,64 Removal of the Boc group from 84 and reacylation with a modified artemisinin gave conjugate 86. While artemisinin (87) itself is a potent antimalarial agent, it has no independent anti-TB activity.…”

Section: ■ Development Of Common Methodologymentioning

confidence: 99%

“…It is tempting to consider that once taken up by Mtb , the Boc form might be converted to the free amine that would then be positively charged and disrupt the binding and/or cell wall structure. Additional extensive SAR of differentially modified mycobactins has been summarized elsewhere. , …”

Section: Development Of Common Methodology For Siderophore Syntheses ...mentioning

confidence: 99%

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Design and Syntheses of New Antibiotics Inspired by Nature’s Quest for Iron in an Oxidative Climate

Miller

Liu

2021

Acc. Chem. Res.

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Conspectus This Account describes fundamental chemistry that promoted the discovery of new antibiotics. Specifically, the NH acidity of simple hydroxamic acid derivatives facilitated the syntheses of novel β-lactams (oxamazins and monobactams), siderophore mimics that limit bacterial iron uptake and bacterially targeted sideromycins (siderophore-antibiotic conjugates). The development of resistance to our current limited set of antibiotic scaffolds has created a dire medical situation. As recently stated, “if you weren’t taking antibiotic resistance seriously before, now would be a good time to start.” A project commissioned by the British government () has released estimates of the near-future global toll of antibiotic resistance that are jaw-dropping in their seriousness and scale: 10 million deaths per year and at least $100 trillion in sacrificed gross national product. The 2020 COVID pandemic confirmed that infectious disease problems are no longer localized but worldwide. Many classical antibiotics, especially β-lactams, previously provided economical cures, but the evolution of antibiotic destructive enzymes (i.e., β-lactamases), efflux pumps, and bacterial cell wall permeability barriers has made many types of bacteria, especially Gram-negative strains, resistant. Still, and in contrast to other therapies, the public expectation is that any new antibiotic must be inexpensive. This creates market limitations that have caused most major pharmaceutical companies to abandon antibiotic research. Much needs to be done to address this significant problem. The critical need for bacteria to sequester essential iron provides an Achilles’ heel for new antibiotic development. Although ferric iron is extremely insoluble, bacteria need micromolar intracellular concentrations for growth and virulence. To this end, they biosynthesize siderophores (Gr. iron bearer) and excrete them into their environment, where they bind iron with high affinity. The iron complexes are recognized by specific outer-membrane transporters, and once actively internalized, the iron is released for essential processes. To conserve biosynthetic energy, some bacteria recognize and utilize siderophores made by competing strains. As a counter-revolution in the never-ending fight for survival, bacteria have also evolved sideromycins, which are siderophores conjugated to warheads that are lethal to rogue bacteria. While none are now used therapeutically, natural sideromycins called albomycins have been used clinically, and others have been shown to be well tolerated and active in animal infection models. Herein we describe practical methods to synthesize new antibiotics and artificial sideromycins with the generalized structure shown above (siderophore-linker drug). Utilizing the molecular-recognition-based siderophore/sideromycin bacterial assimilation processes, it is possible to design both broad spectrum and exquisitely narrow spectrum (targeted) sideromycins and even repurpose older or more classical antibiotics. Relevant microbiological assays, ...

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Section: ■ Development Of Common Methodologymentioning

confidence: 99%

Section: Development Of Common Methodology For Siderophore Syntheses ...mentioning

confidence: 99%

Design and Syntheses of New Antibiotics Inspired by Nature’s Quest for Iron in an Oxidative Climate

Miller

Liu

2021

Acc. Chem. Res.

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“…Based on siderophore's ligand donation ability to coordinate Fe(III), it is classified as hydroxamic acids, catechols, α-hydroxy acids, and aryl oxazolines. [174][175][176] Based on the presence or absence of a 2-hydroxyphenyloxazoline ring, further mycobacterial siderophores are sub-classified into two structural classes, namely, salicylate-based hydrophobic mycobactins and water-soluble carboxymycobactins. 20,157 Salicylate-based mycobactins have a primary nucleus of a 2-hydroxyphenyloxazoline moiety (derived from salicylic acid) linked to an amide bond by an acylated ε-N-hydroxylysine residue.…”

Section: Mycobacterium Iron-scavenging Toolsmentioning

confidence: 99%

TargetingMycobacterium tuberculosisiron-scavenging tools: a recent update on siderophores inhibitors

Kumar,

Adhikrao

2023

RSC Med. Chem.

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Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis

Cited by 2 publications

References 73 publications

Design and Syntheses of New Antibiotics Inspired by Nature’s Quest for Iron in an Oxidative Climate

Design and Syntheses of New Antibiotics Inspired by Nature’s Quest for Iron in an Oxidative Climate

TargetingMycobacterium tuberculosisiron-scavenging tools: a recent update on siderophores inhibitors

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