Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency

Pandey, Apurva; Savino, Chloé; Ahn, Shin Hye; Yang, Zhaoyong; Lanen, Steven G. Van; Boros, Eszter

doi:10.1021/acs.jmedchem.9b01388

Cited by 57 publications

(83 citation statements)

References 76 publications

(143 reference statements)

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“… Structures of Ga complexes of THA‐8 and THA‐9 reported by Pandey et al [48] . Antibacterial parts in red and siderophore parts in blue.…”

Section: Radiolabellingmentioning

confidence: 95%

“…Ga 3+ ions have a similar ionic radius to Fe 3+ , and a similar binding affinity to siderophores. In addition, gallium‐bound siderophores can be recognised by outer and inner membrane transporters [47,48] . Two isotopes of gallium have seen use in radiochemical and medicinal applications: 67 Ga, a gamma emitter ( t 1/2 =3.3 days), and 68 Ga, a positron emitter ( t 1/2 =68 min).…”

Section: Radiolabellingmentioning

confidence: 99%

“…Pandey et al . synthesised THAs of both DFO ( THA‐8 ) and linear desferrichrome ( THA‐9 ; Figure 24) with ciprofloxacin as the antibacterial component, observing high activity versus S. aureus , E. coli , and P. aeruginosa [48] . Uptake studies with 67 Ga were carried out in E. coli , and measured over a two‐hour period.…”

Section: Radiolabellingmentioning

confidence: 99%

“… Results of THA‐8 and THA‐9 radiochemical uptake studies in E. coli for iron‐sufficient (striped bars) and iron‐limited conditions (solid bars). 67 Ga citrate is included for comparison [48] . Measurements were taken after 0.16, 0.33, 0.50, 1 and 2 h.…”

Section: Radiolabellingmentioning

confidence: 99%

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Experimental Methods for Evaluating the Bacterial Uptake of Trojan Horse Antibacterials

2020

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The field of antibacterial siderophore conjugates, referred to as Trojan Horse antibacterials, has received increasing attention in recent years, driven by the rise of antimicrobial resistance. Trojan Horse antibacterials offer an opportunity to exploit the specific pathways present in bacteria for active iron uptake, potentially allowing the drugs to bypass membrane‐associated resistance mechanisms. Hence, the Trojan Horse approach might enable the redesigning of old antibiotics and the development of antibacterials that target specific pathogens. Critical parts of evaluating such Trojan Horse antibacterials and improving their design are the quantification of their bacterial uptake and the identification of the pathways by which this occurs. In this minireview, we highlight a selection of the biological and chemical methods used to study the uptake of Trojan Horse antibacterials, exemplified with case studies, some of which have led to drug candidates in clinical development or approved antibiotics.

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“… Structures of Ga complexes of THA‐8 and THA‐9 reported by Pandey et al [48] . Antibacterial parts in red and siderophore parts in blue.…”

Section: Radiolabellingmentioning

confidence: 95%

Section: Radiolabellingmentioning

confidence: 99%

Section: Radiolabellingmentioning

confidence: 99%

Section: Radiolabellingmentioning

confidence: 99%

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Experimental Methods for Evaluating the Bacterial Uptake of Trojan Horse Antibacterials

2020

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“…This compound was found to possess good antibacterial activity against both Gram(+) and Gram(−) strains (E. coli K12, S. aureus RN4220, P. aeruginosa PA01, and K. pneunomiae CRE-11; MICs = 0.23-12.5 µM) in iron-deficient media. By using radioactive 67 Ga, the group was able to follow the metabolic fate of the compound in mice, opening up the door for potential theranostic applications, with both diagnostic and therapeutic benefits in bacterial infections [59].…”

Section: Bismuthmentioning

confidence: 99%

Metal Complexes, an Untapped Source of Antibiotic Potential?

2020

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With the widespread rise of antimicrobial resistance, most traditional sources for new drug compounds have been explored intensively for new classes of antibiotics. Meanwhile, metal complexes have long had only a niche presence in the medicinal chemistry landscape, despite some compounds, such as the anticancer drug cisplatin, having had a profound impact and still being used extensively in cancer treatments today. Indeed, metal complexes have been largely ignored for antibiotic development. This is surprising as metal compounds have access to unique modes of action and exist in a wider range of three-dimensional geometries than purely organic compounds. These properties make them interesting starting points for the development of new drugs. In this perspective article, the encouraging work that has been done on antimicrobial metal complexes, mainly over the last decade, is highlighted. Promising metal complexes, their activity profiles, and possible modes of action are discussed and issues that remain to be addressed are emphasized.Antibiotics 2020, 9, 90 2 of 24 Metal-containing compounds have played a small but seminal role in medicinal chemistry of throughout the 20th century. An arsenic-containing compound, Salvarsan, was discovered at the beginning of the century and became the first effective treatment of syphilis [9]. It was however the discovery of the anticancer drug cisplatin and its successors that really kickstarted the field of inorganic medicinal chemistry. Even today, platinum-based chemotherapeutics are still used in the majority of cancer treatments [10]. The gold-containing auranofin is an approved drug for the treatment of rheumatoid arthritis and is currently under investigation for its anticancer as well as antimicrobial properties [11][12][13][14][15][16]. Invigorated by these breakthrough successes, the field has expanded to many other elements in the last few decades, with complexes of titanium, iron, ruthenium, gallium, palladium, silver, gold, bismuth, and copper entering clinical trials [17][18][19][20][21][22]. The medicinal applications of these metal complexes range from anticancer to antimalaria over to neurodegenerative diseases. Strangely, antibacterial applications are remarkably sparse in this list and the number of literature reports on metal-based antimicrobials is dwarfed by the much more frequent publications on metal-based anticancer compounds. This is surprising as metals such as bismuth and silver have long been known to possess antibacterial properties. Some medicinal products are currently available. There are however a variety of products, such as silver-coated underwear, with a more dubious scientific basis. Nevertheless, the systematic evaluation of the antimicrobial properties of metal complexes has increased in pace over the last decade, with several reports highlighting the activity and potential modes of action of metal-based antibiotics. This perspective article will discuss the major discoveries in the non-traditional field of metal complex-based antibiotic co...

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Metal Complexes as Resistance Breakers or Metalloantibiotics for Combating Antimicrobial Resistance

Li¹,

Sun²

2022

Encyclopedia of Inorganic and Bioinorganic Chemistry

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The rapid emergence and spread of antimicrobial resistant (AMR) bacterial strains post significant threats to public health globally. Owing to the complexity of AMR, different strategies have been proposed, among which metal‐based strategy has receiving growing attention. Metallodrugs/ metal‐based complexes often exert multi‐targeted mode of action, thus having less likelihood to evolve resistance. Moreover, metal complexes could also target resistant enzymes produced by bacteria, thus might serve as antibiotic adjuvants for rescuing currently used antibiotics. In this encyclopaedia, we summarize the metal‐based strategy for combating AMR including both as resistance breakers or metalloantibiotics. Their underlying mechanisms of actions are also included. We also discuss the future perspective, opportunity and challenges in the field.

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Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency

Cited by 57 publications

References 76 publications

Experimental Methods for Evaluating the Bacterial Uptake of Trojan Horse Antibacterials

Experimental Methods for Evaluating the Bacterial Uptake of Trojan Horse Antibacterials

Metal Complexes, an Untapped Source of Antibiotic Potential?

Metal Complexes as Resistance Breakers or Metalloantibiotics for Combating Antimicrobial Resistance

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