Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

Pandey, Apurva; Śmiłowicz, Dariusz; Boros, Eszter

doi:10.1039/d1sc04283a

Cited by 18 publications

(37 citation statements)

References 44 publications

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“…58 The Ga(III) complex with maltolate 59 was reported to show anti-planktonic properties against S. aureus, while recent success of galbofloxacin, a ciprofloxacincontaining gallium compound, demonstrates success of a combinational approach to gallium-bearing drugs development against S. aureus. 60 In our studies, bacteriostatic properties against S. aureus were observed from all co-crystallization products. Beyond the silver co-crystals (CC-1/2) having good antibiofilm properties, the zinc co-crystal (CC-6) has excellent antibiofilm activity, even though its bacteriostatic activity is less effective.…”

Section: ■ Discussionmentioning

confidence: 55%

Comparison of Antimicrobial and Antibiofilm Activity of Proflavine Co-crystallized with Silver, Copper, Zinc, and Gallium Salts

Lekhan

Fiore

Shemchuk

et al. 2022

ACS Appl. Bio Mater.

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Here, we exploit our mechanochemical synthesis for co-crystallization of an organic antiseptic, proflavine, with metalbased antimicrobials (silver, copper, zinc, and gallium). Our previous studies have looked for general antimicrobial activity for the co-crystals: proflavineHere, we explore and compare more precisely the bacteriostatic (minimal inhibitory concentrations) and antibiofilm (prevention of cell attachment and propagation) activities of the co-crystals. For this, we choose three prominent "ESKAPE" bacterial pathogens of Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. The antimicrobial behavior of the co-crystals was compared to that of the separate components of the polycrystalline samples to ascertain whether the proflavine−metal complex association in the solid state provided effective antimicrobial performance. We were particularly interested to see if the co-crystals were effective in preventing bacteria from initiating and propagating the biofilm mode of growth, as this growth form provides high antimicrobial resistance properties. We found that for the planktonic lifestyle of growth of the three bacterial strains, different co-crystal formulations gave selectivity for best performance. For the biofilm state of growth, we see that the silver proflavine co-crystal has the best overall antibiofilm activity against all three organisms. However, other proflavine−metal co-crystals also show practical antimicrobial efficacy against E. coli and S. aureus. While not all proflavine−metal co-crystals demonstrated enhanced antimicrobial efficacy over their constituents alone, all possessed acceptable antimicrobial properties while trapped in the co-crystal form. We also demonstrate that the metal−proflavine crystals retain antimicrobial activity in storage. This work defines that co-crystallization of metal compounds and organic antimicrobials has a potential role in the quest for antimicrobials/antiseptics in the defense against bacteria in our antimicrobial resistance era.

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Section: ■ Discussionmentioning

confidence: 55%

Comparison of Antimicrobial and Antibiofilm Activity of Proflavine Co-crystallized with Silver, Copper, Zinc, and Gallium Salts

Lekhan

Fiore

Shemchuk

et al. 2022

ACS Appl. Bio Mater.

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“…In a recent study, Boros and her team designed a special version of a siderophore that binds to gallium instead of iron. 5 The bacteria are tricked into transporting the gallium…”

Section: Tricking Bacteriamentioning

confidence: 99%

Booster for Antibiotics

2022

Chemistry & Industry

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“…26 More recently, we demonstrated that the xenometallomycin concept can yield compounds that exceed the potency of the parent antibiotic in vitro and in vivo with the second-generation compound Ga-D5 (Figure 1). 27 However, while synthetic siderophore antibiotic conjugates have been extensively explored, the structure− activity relationship remains difficult to predict. Furthermore, the exact mechanism of the antiproliferative activity of Ga(III) siderophore complexes is not well established and requires further study.…”

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confidence: 99%

“…These conjugates act as “Trojan Horses” and take advantage of the bacterial iron assimilation pathway to deliver antibiotics to the cytoplasm. − Miller, − Nolan, − Bronstrupp, Duhme-Klair, − and Wencewicz ,, have demonstrated that this strategy is not only efficacious but also provides insights into the frequently complex bacterial iron acquisition pathways. Our group focuses on xenometallomycins, which are Trojan horse conjugates that incorporate a nonendogenous metal ion for co-delivery and to enhance bactericidal activity. , We hypothesize that nonendogenous metal ions can exert additional, metal-based toxicity, to further enhance compound potency and attenuate bacterial resistance. We have previously successfully validated this approach with siderophore antibiotic conjugates Ga- D1 , Ga- D2, and Ga- D5 (Figure ), inspired by the structures of the natural product antibiotics salmycin and albomycin. − Our constructs comprised three components: (1) the metal-bound siderophore, (2) a noncleavable linker, and (3) a fluoroquinolone-based antibiotic.…”

mentioning

confidence: 99%

“…Our group focuses on xenometallomycins, which are Trojan horse conjugates that incorporate a nonendogenous metal ion for co-delivery and to enhance bactericidal activity. , We hypothesize that nonendogenous metal ions can exert additional, metal-based toxicity, to further enhance compound potency and attenuate bacterial resistance. We have previously successfully validated this approach with siderophore antibiotic conjugates Ga- D1 , Ga- D2, and Ga- D5 (Figure ), inspired by the structures of the natural product antibiotics salmycin and albomycin. − Our constructs comprised three components: (1) the metal-bound siderophore, (2) a noncleavable linker, and (3) a fluoroquinolone-based antibiotic. Because of the peptidic nature of these constructs, sequence modification is synthetically tractable.…”

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confidence: 99%

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Tracking Uptake and Metabolism of Xenometallomycins Using a Multi-Isotope Tagging Strategy

2022

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Synthetic and naturally occurring siderophores and their conjugates provide access to the bacterial cytoplasm via active membrane transport. Previously, we displaced iron with the radioactive isotope 67 Ga to quantify and track in vitro and in vivo uptake and distribution of siderophore Trojan Horse antibiotic conjugates. Here, we introduce a multi-isotope tagging strategy to individually elucidate the fate of metal cargo and the ligand construct with radioisotopes 67 Ga and 124 I. We synthesized gallium(III) model complexes of a ciprofloxacin-functionalized linear desferrichrome (Ga-D6) and deferoxamine (Ga-D7) incorporating an iodo-tyrosine linker to enable radiolabeling using the metal-binding ( 67 Ga) and the cargo-conjugation site ( 124 I). Radiochemical experiments with Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa wt strains show that 67 Ga-D6/D7 and Ga-D6-124 I/ D7-124 I have comparable uptake, indicating intact complex import and siderophore-mediated uptake. In naive mice, 67 Ga-D6/D7 and Ga-D6-124 I/ D7-124 I demonstrate predominantly renal clearance; urine metabolite analysis indicates in vivo dissociation of Ga(III) is a likely mechanism of degradation for 67 Ga-D6/D7 when compared to ligand radiolabeled compounds, Ga-D6-124 I/D7-124 I, which remain >60% intact in urine. Cumulatively, this work demonstrates that a multi-isotope tagging strategy effectively elucidates the in vitro uptake, pharmacokinetics, and in vivo stability of xenometallomycins with modular chemical structures.

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Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

Abstract: Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(III)...

Cited by 18 publications

References 44 publications

Comparison of Antimicrobial and Antibiofilm Activity of Proflavine Co-crystallized with Silver, Copper, Zinc, and Gallium Salts

Comparison of Antimicrobial and Antibiofilm Activity of Proflavine Co-crystallized with Silver, Copper, Zinc, and Gallium Salts

Booster for Antibiotics

Tracking Uptake and Metabolism of Xenometallomycins Using a Multi-Isotope Tagging Strategy

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